Get Our e-AlertsSubmit Manuscript
Research / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 2016201 |

Zifang Shang, Siew Yin Chan, Qing Song, Peng Li, Wei Huang, "The Strategies of Pathogen-Oriented Therapy on Circumventing Antimicrobial Resistance", Research, vol. 2020, Article ID 2016201, 32 pages, 2020.

The Strategies of Pathogen-Oriented Therapy on Circumventing Antimicrobial Resistance

Received12 Jun 2020
Accepted02 Aug 2020
Published28 Sep 2020


The emerging antimicrobial resistance (AMR) poses serious threats to the global public health. Conventional antibiotics have been eclipsed in combating with drug-resistant bacteria. Moreover, the developing and deploying of novel antimicrobial drugs have trudged, as few new antibiotics are being developed over time and even fewer of them can hit the market. Alternative therapeutic strategies to resolve the AMR crisis are urgently required. Pathogen-oriented therapy (POT) springs up as a promising approach in circumventing antibiotic resistance. The tactic underling POT is applying antibacterial compounds or materials directly to infected regions to treat specific bacteria species or strains with goals of improving the drug efficacy and reducing nontargeting and the development of drug resistance. This review exemplifies recent trends in the development of POTs for circumventing AMR, including the adoption of antibiotic-antibiotic conjugates, antimicrobial peptides, therapeutic monoclonal antibodies, nanotechnologies, CRISPR-Cas systems, and microbiota modulations. Employing these alternative approaches alone or in combination shows promising advantages for addressing the growing clinical embarrassment of antibiotics in fighting drug-resistant bacteria.

1. Introduction

After several decades of successful practices using antibiotics to treat bacterial infectious diseases, the emergence of antimicrobial resistance (AMR) has been recognized as a global public health crisis nowadays [14]. At present, antibiotic-resistant bacteria kill 700,000 people/year worldwide, and the annual death toll caused by AMR is expected to be 10 million by 2050, disbursing about $100 trillion globally [5, 6]. When microbes develop multidrug- or extensively drug resistance (MDR or XDR), they are known as “superbugs” [7]. In facing the rise of antibiotic resistance, the World Health Organization (WHO) released its first priority list of bacteria in urgent need of new antibiotics in early 2017. The list includes 12 dangerous bacterial families that threaten human health, with an objective to guide and promote the research and development of new antibiotics [8]. However, the growth rate of bacterial drug resistance tends to be underestimated and is much faster than the development rate of new antibiotics [9]. This is mainly due to the overuse and misuse of antibiotics to treat infections. Moreover, the development of new antibiotics is slow due to unsatisfactory clinical data, such as unexpected pharmacokinetic parameters, poor stability, low permeability, and lack of in vivo activity and efficiency [10, 11]. Though extensive research is ongoing, very limited new antibiotics can make their way to the patients [12].

Thus, alternative therapeutic approaches to resolve this issue of AMR have attracted increasing research interests in recent years. The principle behind these approaches is to circumvent bacterial resistance against antibiotics by applying antimicrobial compounds or materials directly to specific bacterial species, strains, or infected sites. We believe these strategies can be generally categorized as pathogen-oriented therapy (POT). POT shows a promise in targeting the specific bacteria, increasing effective drug concentration, and reducing the dosage of antibiotics, thus improving the antibacterial efficacy over traditional antibiotics, while reducing nontargeting effect and slowing down the development of drug resistance. These POT strategies include the conjugation among antibiotics, exploitation of antimicrobial peptides (AMPs), adoption of bacteria-specific antibodies, utilization of nanotechnologies, employment of CRISPR-Cas systems, and involvement of microbiota modulation. In this review, we described the research progresses of these POT strategies, elucidating their characteristics and challenges associated with their applications in the future.

2. Antibiotic-Antibiotic Conjugates (AACs)

With the emergence of drug-resistant bacteria, advancing the development of antibiotics is more critical than ever [13]. Creating new antibiotics or developing alternative therapeutic approaches are important to prevent serious drug-resistant bacterial infections [14]. Analysis shows that there are minute amount of new antibiotics targeting most of the world’s dangerous infections [15]. Historical data shows that the success rate of clinical drug development is low that only one-fifth of the products will be approved for phase I clinical trials [16]. To date, about 44 new antibiotics are under clinical development. Of these drugs, only 12 have the potential to address the three key carbapenem-resistant Gram-negative pathogens (viz. Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii) on the WHO’s priority list of antibiotic-resistant Gram-negative pathogens [8, 17]. Researchers have tried hard to develop advanced substitutes by coupling existing antibiotics to overcome drug resistance, known as the antibiotic-antibiotic conjugates (AACs) [1823]. These AACs block the action mode of antibiotic resistance or enhance the overall inhibitory effect of antibiotics [24, 25]. Depending on the functional properties of coupling groups, AACs can be classified into quinolone/fluoroquinolone, aminoglycoside, β-lactamase inhibitor, and macrolide conjugates. Table 1 lists some examples of antibacterial applications of AACs.

Antibiotic conjugatesEvaluated conditionProposed mechanism of actionReference

Quinolone/fluoroquinoloneQuinolone-oxazolidinone (MCB3681)Gram-positive bacterial infectionsInhibit the initiation of bacterial protein biosynthesis[26, 27]
Quinolizine-rifamycin (cadazolid)C. difficile infectionsInhibit protein and RNA synthesis[2830]
Fluoroquinolone-oxazolidinone (CBR-2092)Gram-positive bacterial infectionsInhibit the bacterial DNA replication and DNA-dependent RNA synthesis[31, 32]

AminoglycosideNeomycin B-ciprofloxacinGram-negative bacteria and Gram-positive MRSA infectionsInhibit the activity of DNA gyrase, topoisomerase IV, and protein synthesis[33]
Tobramycin-moxifloxacinPseudomonas aeruginosa infectionsEnhance the permeability of antibiotics to the outer membrane of pathogenic bacteria[34, 35]
Neomycin-sisomicinAminoglycoside-resistant bacteria infectionsInhibit protein synthesis by binding to 16S rRNA[36, 37]

β-Lactamase inhibitorCeftazidime-avibactamComplicated urinary tract infectionsInterfere with bacterial cell wall and peptidoglycan synthesis[22, 38]
Meropenem-vaborbactamComplicated urinary tract infections and acute pyelonephritisVaborbactam potentiates the activity of meropenem, inhibiting the cell wall synthesis and peptidoglycan synthesis[20, 39, 40]
Imipenem-relebactamGram-negative bacterial infectionsRelebactam prevents the hydrolysis of imipenem, exerting imipenem’s bactericidal effect[41, 42]

MacrolideAzithromycin-sulfonamideMacrolide-resistant Streptococcus pyogenes and Streptococcus pneumoniae strainsInhibit mRNA translation and bacterial metabolic processes[43, 44]

2.1. Quinolone/Fluoroquinolone Conjugates

Quinolones/fluoroquinolones are broad-spectrum antibiotics against both Gram-negative and Gram-positive bacteria [4547]. Fluoroquinolones are effective in some life-threatening bacterial infections such as Legionella pneumophila infection. The antibacterial activity of fluoroquinolones is achieved by inhibiting the catalytic cycle of the bacterial topoisomerase, which controls the topological state of the deoxyribonucleic acid (DNA). Bacterial topoisomerase is an indispensable component of basic cellular processes such as DNA replication and transcription, representing a critical targeting site for therapeutic purpose [47].

Oxazolidinones are a class of synthetic antibiotics that inhibit the initiation of protein biosynthesis by binding to the V region of the 23S rRNA catalytic center of the ribosomal 50S subunit in the peptidyl transferase [48, 49]. Oxazolidinones have been demonstrated to be a higher antibacterial activity against Gram-positive bacteria compared with Gram-negative bacteria, and oxazolidinones conjugated with fluoroquinolones using a chemical coupling method increased its antibacterial activity and spectrum [50]. MCB3681 is a quinolone-oxazolidinone conjugate (QOC) developed by Morphochem [26] and exhibited antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.06 to 1 μg/mL against several strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), and vancomycin-resistant enterococci (VRE) [51, 52]. A recent study also reported that MCB3681 displayed good antibacterial activities against Clostridium difficile in vitro with no evidence of drug resistance in the isolated strains [27]. Cadazolid represents a more advanced QOC with an oxazolidinone pharmacophore replaced by a fluoroquinolone moiety [28]. It is initially developed by Actelion Pharmaceuticals to treat C. difficile infection [28, 53], exhibiting antibacterial activity with the MIC range of 0.125 to 0.5 μg/mL [30]. Cadazolid inhibits protein synthesis by oxazolidinone domain and restrains RNA synthesis by quinolone moiety [29, 54]. Another influential quinolone conjugate is quinolone-rifampicin conjugate, CBR-2092, developed by Cumbre Pharmaceuticals through linking 4H-4-oxo-quinolizine and rifamycin SV pharmacophore via a hydrazide group [31, 32]. CBR-2092 showed fairly good antimicrobial properties against clinically isolated Gram-positive bacteria such as MRSA, and its activity was better than quinolone (ciprofloxacin) alone [31]. However, its antibacterial activity against Gram-negative bacteria such as Escherichia coli was considered mild and not comparable to that of ciprofloxacin. Functional studies demonstrated that CBR-2092 exhibited an inhibitory effect on ribonucleic acid (RNA) polymerase, DNA gyrase, and DNA topoisomerase IV [32].

2.2. Aminoglycoside Conjugates

Aside from quinolone/fluoroquinolone conjugates, aminoglycosides are also widely used as conjugated antibiotics [5557]. Aminoglycosides are broad-spectrum antibiotics that are active against most aerobic and facultative anaerobic Gram-negative bacteria [58, 59] by inhibiting protein synthesis by binding to 16S rRNA on ribosomal 30S subunit [60, 61]. However, aminoglycosides are highly hydrophilic [62] and tend to exhibit poor cell permeability. Their pharmacokinetic parameters can be improved by coupling with other types of antibiotics. In particular, aminoglycoside neomycin B was linked with ciprofloxacin via 1,2,3 benzotriazole ligands [33]. The conjugated molecule demonstrated improved antibacterial activity against Gram-negative bacteria, Gram-positive MRSA, and even the most prevalent resistant types related to aminoglycosides, compared with pristine neomycin B. The inhibition mechanism of neomycin B-ciprofloxacin on bacterial protein synthesis is similar to that of neomycin B, while the conjugates exhibited 32 times stronger inhibitory activity on DNA gyrase and topoisomerase IV compared with paternal ciprofloxacin [33]. Besides, tobramycin and moxifloxacin conjugates were used to treat Pseudomonas aeruginosa infections [34]. The coupling of tobramycin and moxifloxacin enhanced the permeability of antibiotics to the outer membrane of pathogenic bacteria. The conjugate protected Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Drug resistance selection studies showed that the use of tobramycin-moxifloxacin conjugate induced lower probability of drug resistance of P. aeruginosa compared to their parental antibiotics [34]. Aminoglycoside-modifying enzymes catalyze phosphorylation, acetylation, or adenylation of hydroxyl and amino groups of aminoglycosides, resulting in the inactivation of aminoglycosides. The coupling of antibiotics with aminoglycoside could inhibit the enzymic modification of aminoglycosides [35, 63]. Hanessian et al. simulated the conjugate of neomycin and sisomicin by cheminformatics, and the MIC values of the conjugate against several aminoglycoside-resistant P. aeruginosa, E. coli, A. baumannii, and S. aureus were reduced by nearly 64 times compared with the parental neomycin B or sisomicin [36].

2.3. β-Lactamase Inhibitor Conjugates

The β-lactamase inhibitors are also a kind of antibiotic with extensive influence. There are mainly three kinds of β-lactamase antibiotic conjugates: avibactam involved conjugates (e.g., ceftazidime-avibactam, aztreonam-avibactam, and ceftaroline fosamil-avibactam), vaborbactam involved conjugates (e.g., meropenem-vaborbactam), and relebactam involved conjugates (e.g., imipenem-relebactam) [21, 6468].

Among the avibactam conjugates, ceftazidime-avibactam has been used in Europe and the United States for the treatment of adults with complicated urinary tract infections (e.g., pyelonephritis and hospital-acquired pneumonia). It is also approved recently by the European Drug Administration for adult patients infected with aerobic Gram-negative bacteria with limited treatment regimen [38, 69]. Meropenem-vaborbactam is the first carbapenem/β-lactamase inhibitor conjugate recently approved by the US Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and acute pyelonephritis [39, 40]. Vaborbactam, also known as RPX7009, is a nontoxic cyclic boric acid β-lactamase inhibitor but lacks antibacterial activity in vitro [70]. The boric acid group covalently bounds to the serine side chain at the β-lactamase catalytic site [71], inhibiting the activity of β-lactamase. Vaborbactam has anti-Ambler class A and C enzyme activities [72]. It has been shown to inhibit various class A carbapenem enzymes (KPC-2, KPC-3, KPC-4, BKC-1, FRI-1, and SME-2), class A extended-spectrum β-lactamases (ESBL) (CTX-M, SHV, and TEM), and class C cephalosporinase (CMY, P99). However, it has no inhibitory activity against D-type carbapenem (OXA-48) or metallo-β-lactamases (NDM, VIM, and IMP) [65, 73]. Relebactam-imipenem is currently being evaluated for the treatment of Gram-negative bacterial infections, including hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, complex intraperitoneal infection, and urinary tract infection caused by MDR pathogens, especially P. aeruginosa and carbapenemase-producing E. coli, K. pneumoniae, and Enterobacter [7476]. Prescription of imipenem combined with relebactam for the treatment of Gram-negative bacterial infections is currently in phase III of a clinical trial [41].

2.4. Macrolide Conjugates

Macrolide is a general term for natural products of polyketides and their semisynthetic derivatives [77]. They are composed of macrocyclic lactone of different ring sizes and are attached with one or more deoxy sugars or amino sugars. Macrolides play an important role in inhibiting bacteria via reaction with bacterial 50S ribosomal subunits and interfering with the protein synthesis pathway [78]. Due to their high-affinity binding ability with bacterial ribosomes and the highly conserved structure of ribosomes in almost all bacterial species, macrolides are endowed with broad-spectrum antibacterial properties as antibiotics [79]. Since the discovery of macrolide erythromycin in 1950, many derivatives have been synthesized, including the famous azithromycin and clarithromycin [8083]. The emergence of many macrolide-resistant bacterial strains and the long-term laborious development process of conventional new drugs have rendered the development in creating new conjugates based on existing drugs. Through this means, the coupled molecules could synergistically possess unique biological characteristics and play a better role in antibacterial clinical use.

Azithromycin-sulfonamide showed good antibacterial activity in vitro with MIC values ranging from 0.5 to 2 μg/mL against macrolide-resistant Streptococcus pyogenes and Streptococcus pneumoniae strains, but inactive against Gram-negative H. influenzae and E. coli strains [43]. The macrolide-quinolone conjugates have improved antibacterial activity against drug-resistant strains, and further modification enhanced their effectiveness [44]. These molecules have made a breakthrough in antibacterial activity, showing better antibacterial activity than telithromycin, successfully inhibiting various macrolide-resistant bacterial isolates. The optimized conjugate showed fairly good antibacterial activities against MDR S. pneumoniae and S. pyogenes with a resistance phenotype of less than 0.125 μg/mL MIC.

In summary, AAC can be composed of two antibiotics with both of their antimicrobial activity for exerting a synergistic effect, or be composed of antibiotics with their bioactive adjuvants, such as inhibitors of efflux pumps or antibiotic-modifying enzymes, for enhancing the effect of antibiotics and improving their pharmacokinetic parameters. Despite these advantages, AAC pays more attention to whether it has superior or at least no inferior antibacterial activity compared with classical combination therapy or parental generation, but most current studies are lack of systematic research on the occurrence and mechanism of drug resistance.

3. Antimicrobial Peptides (AMPs) in Combatting AMR

3.1. AMPs

AMPs are oligomers of amino acids that have homogeneous structural groups, which are differed from the small molecule of antibiotics described in the previous section. Due to AMPs’ significant antibacterial role in host organisms, a large number of clinical trials have demonstrated AMPs as promising candidates for AMR [84, 85]. Depending on the structural characteristics of AMPs, they are classified into four types: α-helix, β-sheet, extended, and cyclic. Most natural AMPs are modified in order to improve their metabolic stability, bioavailability, safety, immunogenicity, etc. [8688]. Most AMPs are cationic and amphiphilic, allowing them to penetrate and/or destroy bacterial membranes. Identifying the optimum ratios of cationic and hydrophobic amino acid residues is important for maintaining low hemolysis and high antibacterial activity [89, 90]. AMPs target on the bacterial membrane or intracellular components to achieve antibacterial effect [91, 92]. Interestingly, AMPs do not interact with specific targets in pathogens [93], which render the evolution of pathogen resistance to AMPs at a relatively slow rate. Few cases of drug resistance to AMPs have been reported, particularly tyrothricin, which has been clinically used for more than 60 years [94]. Since 1939, a natural antimicrobial peptide named gramicidin has been identified from Bacillus brevis that exhibited antibacterial activity against Gram-positive bacteria in the infected wound sites in guinea pigs as a substitute for synthetic antibiotics [95]. Since then, researchers have developed various types of AMPs to combat the prickly problem of antibiotic resistance, e.g., α-helix (magainin [96], LL-37 [97, 98], and hCAP18 [99]), β-sheet (defensin [100], protegrin [101], and tachyplesin [102]), and extended (indolicidin [103] and bactenecin [104]).

Natural AMPs are easily degraded by proteolytic enzymes or peptidases or cleared by the liver and kidney in the body, hindering their development in clinical treatment against pathogens [105, 106]. To improve the metabolic stability and bioavailability of natural AMPs, modification and synthesis of AMPs have been adopted. Modification approaches can be classified into three forms: cyclization [107109], replacement of noncanonical residues [110112], and N/C-terminal modifications [88, 113115]. Most oral active peptides are cyclic, including the well-known potent peptide antibiotics such as bacitracin A [116, 117], colistin [118, 119], gramicidin [120], and polymyxins B1 and B2 [121, 122], demonstrating that cyclization of AMPs is effective [123]. Cardoso et al. have pioneered the use of D-amino acids in place of L-amino acids to improve the bioavailability of AMPs. The modified AMPs had higher proteolytic stability while having similar antibacterial activity as the original AMPs [124]. Isomerization has since become a popular method to increase the stability of AMPs against proteolysis. N/C-terminal acetylation, amidation, or addition of hydrophobic oligomers can also be employed to increase AMPs’ resistance to peptidase or protease hydrolysis in vivo. Lewis et al. successfully extracted teixobactin from the Gram-negative bacterium Eleftheria terrae with the new iChip [125] technology [126]. Teixobactin is a compound that potently inhibits the growth of S. aureus (Figure 1). It is a polypeptide consisting of 11 amino acids, comprising nonprotein amino acid enduracididine, methylphenylalanine, and four D-amino acids (Figure 1(a)).

Teixobactin displayed a fairly good inhibitory effect on Gram-positive bacteria (including the difficult-to-treat Enterococcus and Mycobacterium tuberculosis) with MIC value of <1 μg/mL for most bacteria (Figure 1(b)). It particularly inhibited the growth of C. difficile and Bacillus anthracis with MIC values of 5 and 20 ng/mL, respectively. It showed higher bactericidal activity against S. aureus compared to vancomycin in killing late exponential phase populations. Teixobactin also displayed bactericidal activity against vancomycin-intermediate S. aureus (VISA) (Figure 1(c)). However, teixobactin had no activity against most Gram-negative bacteria. It only had an inhibitory effect on a mutant E. coli that lacks the outer membrane permeation barrier. Surprisingly, no drug-resistant strain, hemolysis, and genotoxicity in vivo were detected for the use of teixobactin [126]. To some extent, teixobactin has excellent antibacterial activity after modification via cyclization, replacement of noncanonical residues, and N-terminal modifications of amino acids, showing promising roles in POT in the future.

Darobactin is a modified heptapeptide with an amino acid sequence of W1-N2-W3-S4-K5-S6-F7W1-N2-W3-S4-K5-S6-F7. It is a potential new antibiotic screened from Photorhabdus isolates (Figure 2) [127]. The amino acids within darobactin are linked through two macrocycles. Darobactin demonstrated a fairly good effect on Gram-negative pathogens (E. coli, K. pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, etc.) without cytotoxicity in vitroand in vivo (Figures 2(a) and 2(b)). Mechanism study revealed that darobactin binds to the BamA protein located in the outer membrane of Gram-negative bacteria (Figure 2(c)), destructing the outer membrane structure and inducing the death of bacteria (Figure 2(d)). On the other hand, Luther et al. synthesized a series of antibiotics inspired by the scaffold of natural products. These chimeric antibiotics contain β-hairpin macrocycles linked to the macrocycles found in the natural products polymyxin and colistin families (Figure 3(a)) [128]. The optimized derivatives have bactericidal activity against a wide range of Gram-negative ESKAPE pathogens, including MDR and EDR E. coli strains (Figures 3(b) and 3(c)). It also exhibited low cytotoxicity to mammalian cells, having a low possibility in inducing drug resistance in all tested bacterial strains. The synthesized antibiotics also maintained good levels of potency in the presence of human serum, showing decent safety and pharmacokinetic characteristics. Mechanism study demonstrated that they bind to the outer membrane protein BamA, leading the abnormal growth of bacteria and eventually causing the death of bacteria. These derivatives showed strong in vivo efficacy in mouse models of peritonitis induced by colistin-resistant E. coli strains containing mcr-1 and mcr-3 drug-resistant genes and in mouse models of thigh infected with drug-resistant E. coli, A. baumannii, and P. aeruginosa. Table 2 lists some selected AMPs’ development at different clinical status.

PeptideDescriptionEvaluated conditionClinical trial phaseCompanyProposed mechanism of action

AA139Originates from arenicin-3Urinary tract infectionPhase IAdenium BiotechInterruption of phospholipid transportation pathways, membrane dysregulation
AB103A peptide mimetic of CD28Necrotizing soft tissue infectionsPhase IIIAtox BioAttenuate cd28 signaling during bacterial infection
DalbavancinSemisynthetic lipoglycopeptideGram-positive osteoarticular infectionsPhase IVInfectious Diseases Physicians, Inc.Inhibit transglycosylation and transpeptidation for cell-wall synthesis
PexigananAnalogue of magainin-2Infected diabetic ulcersPhase III (failed)Dipexium Pharmaceuticals, Inc.Cell membrane disruption
LL37A 37 amino acid cationic peptide of the hCAP18 proteinVenous leg ulcers and diabetic foot ulcersPhase IIaPromore PharmaModulate the inflammatory phase
SAAP-148An LL-37-derived peptideAtopic dermatitis and methicillin-resistant staphylococcus aureus infectionsPreclinicalMadam TherapeuticsCell membrane modulators
OritavancinA semisynthetic lipoglycopeptideAcute bacterial skin and skin structure infectionsPhase IIIMelinta Therapeutics, Inc.Inhibit cell wall biosynthesis
PAC-113A 12-amino acid peptide derived from the histatinCandidiasis infectionPhase IIbPacgen Biopharmaceuticals CorporationCell membrane permeability enhancers; reactive oxygen species stimulants
SGX942Synthetic 5-amino acid peptideOral mucositisPhase IIISoligenixTarget the intracellular control pathways
Murepavadin (POL7080)A 14-amino-acid cyclic peptide based on protegrin-1Pseudomonas infectionsPreclinicalPolyphor Ltd.Target the Gram-negative bacterial outer membrane proteins
Novexatin (NP213)A cyclic arginine-based heptamerToenail infectionsPhase I/IIaNovaBiotics Ltd.Disrupting bacterial cell membranes
hLF1-11The first eleven amino acids of the natural human lactoferrinInfection of bone marrow stem cell transplantationsPhase IIAm-PharmaModulation of the immune system
BrilacidinA mimic of defensinAcute bacterial skin and skin structure infectionPhase IIIInnovation Pharmaceuticals Inc.Disrupting bacterial cell membranes
PXL01A synthetic peptide derived from the human lactoferricin peptidePostsurgical adhesions and scarsPhase IIIPromore PharmaImmunomodulation and enhancement of fibrinolytic activity
OG716A derivative of mutacin 1140Clostridium difficile infection in enteritisPreclinicalOragenics, Inc.Transmembrane lipid II-mediated pore formation
OmigananA synthetic 12 amino acid peptide, analogue of indolicidinCatheter infectionsPhase IICutanea life sciencesCell membrane permeability enhancers

3.2. AMP-Antibiotic Conjugates

Most microbial surface contains heaps of negatively charged compounds such as lipoteichoic acid and lipopolysaccharide [129131], while mammal cell surfaces are rich in zwitterionic phospholipids, cholesterol, and sphingomyelin compounds [132, 133]. This major difference allows AMPs to selectively target microbial cells, providing the foundation for the design and development of AMP conjugate drugs. From the perspective on antibacterial mechanism, both compounds of conjugated AMPs would have contributed antibacterial activities, possibly enhancing the overall effect. The AMP moieties could possibly increase the accumulation of the second conjugated group through different carrier mechanisms, ideally enhancing the antibacterial activity against Gram-positive and Gram-negative bacteria [134, 135]. As for AMP-antibiotic conjugates, AMPs could act as uptake enhancers and/or antimicrobial agent, which is a promising strategy for POT.

Magainin II is a typical representative of α-helical AMP, which is isolated from Xenopus laevis. It mainly binds to the surface of the anionic lipid layer through electrostatic interaction [136], resulting in membrane thinning and destruction and inducing pore formation and lysis of cells [137, 138]. The conjugate magainin II-vancomycin demonstrated higher activity against vancomycin-resistant Enterococci compared to vancomycin alone [139]. Other peptides such as M33, indolicidine, or transactivating transcriptional activator (TAT) have been conjugated with levofloxacin for POT [140]. M33 is a branched synthetic peptide with a broad-spectrum antibacterial effect by binding lipopolysaccharide (LPS) on the surface of Gram-negative bacteria [141]. Experimental results suggested that the activity of M33-levofloxacin conjugate was not superior to that of M33, but the combination of M33 with levofloxacin was better than that of M33 and levofloxacin alone. Indolicidine is an AMP-rich cationic tryptophan in bovine neutrophils and is active against both Gram-positive and Gram-negative bacteria [142, 143]. Transactivating transcriptional activator (TAT) is a positively charged dodecapeptide derived from human immunodeficiency virus 1 (HIV-1). TAT is rich in arginine and lysine, enhancing cell membrane permeability [144]. Indolicidine-levofloxacin and TAT-levofloxacin conjugates have also been reported to have similar antibacterial properties [145].

To improve the selective antibacterial effect, oligonucleotides and antibiotics can be conjugated. Triclosan is a sulfuryl-CoA reductase inhibitor and has been reported that it is not able to inhibit Toxoplasma gondii [146]. By incorporating oligoarginines, the conjugate oligoarginines-triclosan demonstrated an inhibitory effect against the growth of Toxoplasma gondii in vitro and in vivo. Besides, Schmidt et al. coupled the penetrating peptide Pen with tobramycin [147]. The conjugates not only retained high antibacterial activity of tobramycin but also had improved efficiency in killing S. aureus and E. coli. When 25 μM of tobramycin was used in conjugation with peptide Pen, the efficiency of the conjugates in killing S. aureus and E. coli was increased by 106 times and 104 times, respectively. Excitingly, there were no side effects induced on eukaryotes. Hansen et al. investigated the coupling of antisense peptide nucleic acid (PNA) with AMP. PNA is a new class of antibiotics that inhibit the growth of bacteria by specifically knocking out the expression of essential genes [148]. Studies have shown that some AMPs such as buforin 2-A (BF2-A), drosocin, Pep-1-K, and KLW-9 with intracellular antimicrobial functions can be used as effective carriers for bacteria to deliver antibacterial PNA and target the acpP gene essential for fatty acid synthesis. Pep-1-K and KLW-L-9 have been identified as peptide moieties that can display normal activity without relying on the bacterial endomembrane transporter SbmA at MIC concentration of 2-4 mM [148].

In summary, using AMPs alone as antimicrobial agents or AMPs as uptake enhancers is a promising strategy, which can not only kill extracellular pathogens but also target intracellular pathogens. In fact, the AMPs component of the AMP-antibiotic conjugates may increase the antibacterial activity of the drug against intracellular microorganisms and reduce the cytotoxicity to mammalian cells. Despite the above advantages, some of the disadvantages of AMP conjugates, including high production cost, low oral bioavailability, poor metabolic stability, and undesirable serum stability and immunogenicity, still need to be further studied before they can be used in vivo. In general, this drug delivery strategy is expected to provide new treatment options for the fight against pathogen resistance.

4. Antibody Therapy in Combatting AMR

4.1. Monoclonal Antibody (mAb) Therapy

The therapeutic potential of serum therapy, which essentially uses antibodies in the plasma of rehabilitated patients to neutralize bacteria, has been recognized since late 19th century when Shibasaburo Kitasato and Emil von Behring used serum from patients infected with Corynebacterium diphtheria and Clostridium tetanus to prevent infection in other patients or horses [149]. In the early 20th century, people began to use serum therapy to treat viral and bacterial diseases [150]. With the emergence of antibiotics in the 1930s, serum therapy suffered an eclipse [151]. As antibiotics are easier to manufacture and the cost of production is cheaper, they have led the development in fighting bacterial infections over the past 80 years [152]. However, the widespread emergence of antibiotic-resistant bacteria poses a major threat to the public health. Moreover, most bacterial infections are caused by antibiotic-resistant pathogens. The development of antibody therapy is one of the promising alternatives for antibiotics to have a direct clinical impact due to the unique advantages of mAbs in recognizing specific pathogens [153156]. mAb usually target antigens exposed on the surface of the pathogen or toxins secreted by the pathogen, which are not targeted by antibiotics. Unlike broad-spectrum antibiotics, which have no selectivity on bacterial composition, mAb is highly specific and exert ecological protection effect on nontargeted bacteria. mAb also helps in reducing the usage of conventional antibiotics, diminishing the selection pressure for resistant strains.

There are several mechanisms of action for the antibacterial effect of mAb. The first proposed mechanism involves mAb bind to the target antigen on the surface of the pathogen, changes the conformation of the fragment crystallizable (Fc) region [157], and promotes complement component 1q (C1q) to recognize and bind to the antibody-binding site. Subsequently, the complement activation system is activated to form a membrane attack complex [158], which eventually leads to bacterial cell lysis and death [158160]. mAb 17H12 and 8F12 have been isolated from mice inoculated with a mixture of anthrax protective antigen coupled with K. pneumoniae capsular polysaccharide (CPS). These two mAbs specifically bind to the CPS epitope of the carbapenem-resistant K. pneumoniae strain ST258 [161], promoting the phagocytosis and cellular cytotoxicity of human neutrophils and mouse macrophages against K. pneumoniae. Chimeric mAb 2C7 with a E430G Fc (2C7-E430G Fc) also demonstrated a similar mechanism of killing bacteria [162]. Besides, mAb can also promote the killing of the opsonophagocytic through the binding of the Fc region with the receptor on the surface of phagocytes [163, 164]. MRSA is a common cause of deadly blood infections. It produces coagulase (Coa) to activate the host of prothrombin fibrinogen [165]. The R domain in the C terminal of Coa comprises 27 amino acid residues with conservative tandem repeat sequences, which binds fibrinogen onto the surface of MRSA to protect pathogens from phagocytosis by immune cells [166, 167]. Thomer et al. immunized mice with full-length Coa expressed by S. aureus as an antigen and obtained mAb 3B3 [168]. It was demonstrated that the R domain of Coa bound onto 3B3, inhibiting Coa binding to fibrinogen and triggering phagocytosis of Staphylococcus. Nielsen et al. extracted mAb C8 by inoculation of mice with a sublethal dose of highly toxic A. baumannii strain [169]. C8 targeted and bound to the carbohydrate of bacterial surface capsule to enhance opsonophagocytosis. After humanized, C8 significantly increases the phagocytosis of A. baumannii. Finally, mAb neutralizes the activity of bacterial toxins by inhibiting the binding of bacterial exotoxin molecules with host cell targets or blocking their polymerization with other toxin subunits [170172]. Many pathogenic bacteria cause diseases by releasing toxins, and the use of therapeutic antibodies that neutralize these toxins is an integral part of the treatment for infections. Anthrax toxin is a three-component protein exotoxin composed of a protective antigen and two enzymes (edema factor and lethal factor) segments [173], working together to suppress the immune response and kill the host cells. Obiltoxaximab (Elusys Therapeutics) and Raxibacumab (AstraZeneca) are obtained via the phage display technique that can neutralize the protective antigen of B. anthracis, inhibiting the lethal effect of anthrax toxin [174, 175]. Interleukin A/B (LukAB) is a recently discovered toxin in S. aureus infections, which kills human primary phagocytes and is the main factor for human monocyte death [176]. Three monoclonal antibodies (SA-13, SA-15, and SA-17) were obtained from B cells of a 12-year-old patient with S. aureus osteomyelitis via the hybridoma technique [177] and were reported to possess a unique neutralization mechanism against the virulence factor LukABv of S. aureus and demonstrated competent efficacy in vivo. Table 3 shows antibodies against pathogenic bacteria in clinical research.

AntibodyEvaluated conditionTargetClinical trial phaseMethod of generationReference

MEDI4893S. aureus pneumoniaAlpha toxinPhase IIbHybridoma technology[178180]
ASN100Staphylococcal infectionsAlpha toxin, leukocidinsPhase IIYeast surface display[181, 182]
AR-301S. aureus lung infectionsHuman leukocyte antigenPhase IIIScreening human B-cells of convalescent pneumonia patients[183]
514G3S. Aureus bacteremiaSpAPhase IIB-cell isolation[184, 185]
AR-101P. aeruginosa infectionsLPSPhase IIaScreening of the B-cell repertoire[186]
MEDI3902P. aeruginosa pneumoniaPcrV and PslPhase IIPhage display[187189]
KB001-AP. aeruginosa infectionsPcrVPhase IIHybridoma technology[190, 191]
RaxibacumabAnthraxProtective antigenFDA approvedPhage display[192]
AnthimAnthraxProtective antigenPhase IMouse hybridoma[193]
BezlotuxumabC. difficile infectionsToxin BFDA approvedMouse immunization[194, 195]
ShigamabsShiga toxin-producing infectionsShiga toxin 1 and 2Phase IIMouse hybridoma[196]

4.2. Antibody-Antibiotic Conjugates

The design of antibody-antibiotic conjugates is similar to the design of antibody-drug conjugates (ADCs) [197200] for the treatment of tumor cells. Using antibodies specific for bacterial cell surface antigens, these conjugates were endowed with specificity and efficacy that cannot be afforded by traditional drugs.

Genentech has reported a striking strategy on treating intracellular persistent S. aureus infections recently (Figure 4) [155]. A group of specific anti-S. aureus antibodies had been screened against several MRSA strains derived from 40 patients. The specific antibodies bind selectively to glycopolymers on the outer layer of Gram-positive bacteria known as wall-teichoic acids (WTAs). The verified antibodies were coupled with rifamycin derivative (rifalogue) to kill MRSA hidden in cells. Rifalogue was attached to the specific antibody of WTA with a linker, enabling it to be cleaved by lysosomal cathepsin and subsequently the releasing of it (Figure 4(a)). Unlike the mixture of rifampicin and unconjugated anti-MRSA antibody, the antibody-antibiotic conjugate significantly reduced the transfer of S. aureus from infected peritoneal cells to uninfected osteoblasts in the presence of vancomycin (Figure 4(b)). Mice injected with vancomycin and intracellular methicillin-resistant S. aureus formed bacterial colonies in the brain but were effectively eliminated in mice treated with vancomycin and the conjugate (Figure 4(c)). In addition, a single dose of the conjugate also helped in preventing kidney colonization, whereas unconjugated rifalogue, unconjugated WTA-specific antibody, or noncleavable conjugate treatments in the control group did not (Figure 4(d)).

In summary, mAb therapy is a promising way to reduce drug resistance and economic burden of clinical infectious bacteria in the current situation of widespread antibiotic resistance and rarely developed new antibiotics for the treatment of drug-resistant bacteria. Although the development of mAb is increasing over time, only a few mAbs have been evaluated in clinical studies; more research into mAb is needed to expand the potential of it in combating AMR. The strategy using antibody-antibiotic conjugates for treating infectious diseases is an exciting approach by combining the pharmacological properties of antibodies and antibiotics into a single molecule. Given that some of the effective antibiotics in clinical trials fail in vivo due to poor pharmacokinetics or undesirable host toxicity, antibody-antibiotic conjugates can often help overcome these problems by targeted delivery of antimicrobial compounds to infected cells. Therefore, although this combination is technically challenging and expensive, its potential for specialized treatment of intracellular pathogens is very promising.

5. Nanotechnology in Combatting AMR

Advances in nanotechnology open up promising antimicrobial nanotherapies, particularly in the development of nanoparticles in drug delivery, have had a major impact in combating AMR [201206]. Nanoparticles (NPs) are tiny particles less than 100 nm in at least one dimension, and their typical small size allows them to be absorbed by phagocytes and introduce antimicrobial agents into the mammalian cells, targeting intracellular pathogens [207]. NPs have high specific surface areas and functional structures, enabling the highest possible loading capacity of drug molecules [208, 209]. In addition, the high adaptability of NPs to drug molecules (i.e., hydrophobic and hydrophilic) and their high stability in physiological fluids permit controlled biodegradation and minimize adverse side effects [210]. These desirable characteristics allow improvement in bioavailability and therapeutic effect of antibacterial drugs, making NPs as promising drug carriers. Due to their inherent antimicrobial properties and their admirable physicochemical (delivery or maintenance of antimicrobial agents at specific sites of infection) properties, NPs have attracted much attention in POT research.

5.1. Antimicrobial NPs

NPs such as silver, copper, and gold show good antibacterial activity and have a wide range of applications [211213]. However, these inorganic NPs do not exhibit antibacterial activity with selectivity, rendering the development of composite NPs. Graphene oxide-silver (GO-Ag) NPs differentially inhibited Gram-negative E. coli and Gram-positive S. aureus [214]. GO-Ag NPs exhibited a bacteriostatic effect for E. coli and S. aureus by destroying the integrity of the bacterial cell wall and inhibiting the cell division cycle, respectively. Aminosaccharide-based gold NPs were developed to work according to the difference in cell wall structure between Gram-positive and Gram-negative bacteria [215]. This NP composite demonstrated narrow-spectrum antibacterial activity, restricting the growth of Gram-positive bacteria by specifically inhibiting the biosynthesis of Gram-positive bacteria cell wall. It can minimize the damage on probiotics and prevent dysbacteriosis. Aminosaccharide-based gold NPs had also shown great potential for wound healing application [215].

At normal physiological conditions, pathogen cell walls are generally negatively charged [216], and the electrostatic interactions of the bacterial cell wall can be targeted by designing positively charged NPs. A cationic polymer such as chitosan can be incorporated into NPs’ systems in order to improve the efficiency of antibacterial activity. In a study involving grafting of cationic polymer chitosan and small molecule 2-mercapto-1-methylimidazole onto the surface of gold nanoparticles, the resulting NPs bestowed multivalent interaction with a bacterial membrane with improved antibacterial activity [217]. The cationic polymer coatings targeted selected bacteria and exhibited antibacterial activity by destroying the bacterial cell plasma membrane, inhibiting bacterial proliferation, and preventing biofilm formation via strong electrostatic interactions with the negatively charged bacterial membrane. The composite NPs were capable of adhering to the surface of mature biofilms and inactivated the surrounded bacterial cells, causing the biofilm to rupture [216]. Most importantly, chitosan-based gold NPs displayed great biocompatibility by exhibiting selective antimicrobial activity on bacteria but remaining harmless to mammalian cells.

5.2. Antibiotic-Delivering NPs

NPs play a promising role in the targeted delivery of antibiotics, providing a platform for POT to fight against the dilemma of antibiotic resistance. Precise drug delivery can be achieved through stimuli-responsive NPs. As a result of the combined activities of bacterial metabolism and host immune response, acidification can occur at the infected sites when hosts were infected by bacteria [218, 219]. The efficacy of the delivery and release of drugs can be significantly hindered by the acid environment. To tackle the problem, surface charge-switching polymeric NPs were developed using poly(d, l-lactic-co-glycolic acid)-b-poly(l-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) [220]. The NPs were at first kept at pH 7.4 (negative charge) to prevent it from interacting with nontargeted objects. Under low pH condition, the imidazole group in the PLH can be partially protonated and bind tightly with bacteria for drug delivery. Delivery of drugs can be terminated by alleviating the pH value of the environment. This represents alternatives for targeted therapy with acidic Gram-positive, Gram-negative, or plague infections [220].

There are other unique infectious microenvironments that can be used as a targeted means of antibiotics at the sites of bacterial infections. Recent research has looked into antibiotic treatment strategy involving macrophages for bacterial infections [221]. Mannose ligands were grafted onto the polyphosphoester core made of polyethylene glycol (PEG) to form nanogels, and these nanogels can be used as drug carrier-targeted macrophages. It was reported that macrophages express a high level of mannose receptors [222], allowing drug accumulation at the bacterial infection sites and subsequent degradation of the NPs by bacterial generated active phosphatase or phospholipase. The nanogels with antibiotics were reported to effectively inhibit the growth of MRSA. The survival rate of zebrafish infected with MRSA showed that mannosylated nanogel-encapsulated vancomycin was better than the treatment with nonmannose-treated nanogels. Mannosylated nanogels have successfully attained both the ability to target macrophages and lesion site-activatable drug release properties, enhancing the inhibition of bacterial growth [221].

Precise drug release through NPs with targeted molecules is also an effective antimicrobial treatment. Ghanbar et al. achieved selective bactericidal efficacy against MRSA by encapsulating biocide (C17) in solid lipid nanoparticles (SLNPs) and coupling MRSA-specific antibody (Ab) to the surface of the SLNPs [223]. The antibacterial activity of SLNPs loaded with Ab (C17-SLNP-Ab) was better than SLNPs loaded without Ab (C17-SLNP) and C17-SLNP with nonspecific IgG (C17-SLNP-IgG). C17-SLN-Ab showed selective toxicity to MRSA in the coculture assay of MRSA/fibroblast. The toxicity of C17-SLN-Ab to MRSA was higher than that of P. aeruginosa. The authors have also successfully adjusted the selectivity from MRSA to E. coli by changing C17 to K12, showing the versatility of this new strategy [223]. Hussain et al. obtained a S. aureus-specific 9-amino-acid oligopeptide by phage display technology (Figure 5) [224]. The obtained CARGGLKSC(CARG) was attached to NPs loaded with vancomycin (Figure 5(a)), enabling nanoparticles to specifically target S. aureus-infected tissues, achieving precise drug delivery, reducing the systemic dose needed, minimizing side effects, and enhancing antimicrobial activity. CARG specifically bound to S. aureus and selectively accumulated in the lungs and skin of mice infected with S. aureus (Figure 5(b)) rather than in noninfected tissues and tissues infected with Pseudomonas bacteria (Figures 5(c) and 5(d)). In vivo experiments have shown that the NPs with specific oligopeptide are more effective in inhibiting S. aureus infection than equivalent doses of nontargeted vancomycin NPs or without vancomycin (Figure 5(e)) [224]. This strategy can reduce the dosage of antibiotics needed and attenuate side effects and the risk of drug resistance.

Furthermore, Zhang et al. developed bioresponsive NPs for targeted delivery of drugs which achieved effective control and treatment of sepsis [225]. A pH/enzyme-sensitive amphiphilic polymer was synthesized and self-assembled to form nanomicelles. These nanomicelles effectively loaded antibiotics ciprofloxacin (CIP) and anti-inflammatory drugs ((2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide). The surface of the drug-loaded NPs was further modified by incorporating intercellular adhesion molecule-1 (ICAM-1), a targeting antibody via specific action of biotin-avidin. Multiple animal models were studied to elucidate the controlled release mechanism of drug delivery at infectious microenvironments (IMEs). In a mouse model of sepsis infected by P. aeruginosa, the developed NPs effectively eliminated invading bacteria and alleviated inflammation, thereby increasing the survival rate of mice. This study provides new insights on the mechanism of NPs in the treatment of infectious diseases and presents new ideas for developing new functional nanomaterials based on disease characteristics.

In brief, with rapid development in nanotechnology and a more in-depth study of infectious diseases that have been conducted in recent years, antibacterial drugs have made significant progress in targeted delivery. Most of the current research focuses on the fundamentals of nanoparticle-based pathogen-oriented therapy, mainly targeting to improve the therapeutic effectiveness and reduce drug resistance. At present, antimicrobial NPs are still rarely used in clinical settings; yet, they have great potentials in the future treatment of various infectious diseases.

6. CRISPR-Cas System in Combatting AMR

6.1. CRISPER-Cas

The CRISPR system is an acquired immune defense mechanism that evolved from the constant attack of foreign viruses or plasmids [226]. It was originally discovered in bacteria and archaea. To date, more than 40 different Cas protein families have been reported, each of which differs significantly in the synthesis of crRNA, the integration of spacer sequences, and the way in which foreign DNA is cleaved [227]. The CRISPR/Cas system can be classified into two classes and six types: class one which has a more complex structure (types I, III, and IV) and class two that has a simpler structure multiple (types II, V, and VI). Class one Cas proteins are involved in the process of exogenous DNA recognition and cleavage, while class two is recognized and cleaved by a single multidomain enzyme [228]. In eukaryotic cells, cleaved DNA is efficiently repaired by ubiquitous mechanisms such as homologous recombination or nonhomologous end joining [229]. In contrast, bacteria cannot perform nonhomologous end-joining mechanism and cannot repair DNA double-stranded cleavage by CRISPR/Cas nuclease, triggering their death. Using the CRISPR/Cas system to precisely cut the DNA of bacteria can lead to the development of a new, efficient, and specific method for eliminating bacteria [230].

Citorik et al. utilized their laboratory-developed phage-delivered CRISPR-Cas9 system (Figure 6) to specifically remove antibiotic-resistant genes such as NDM-1 which allows bacteria to develop resistance to a variety of β-lactam antibiotics (Figure 6(a)) [231]. In a group of three different drug-resistance E. coli strains, they were able to selectively eliminate the targeted strains while maintaining the integrity of other bacteria (Figures 6(b) and 6(c)). Bikard et al. explored the same system in inhibiting S. aureus [232]. Destruction of S. aureus plasmids with resistance genes was achieved without damaging the nontoxic Staphylococci. The CRISPR-Cas9 system had shown a good effect of killing S. aureus in vivo in the mouse skin colonization model.

However, phage-based delivery systems are still inadequate in terms of effectiveness and safety [233]. More recently, researchers have engineered “pathogenicity islands” (PIs) from bacterial DNA, which are the genes unique to the pathogen that evolved from the virus and stays permanently in the virulent bacteria. A CRISPR/Cas9 module capable of specifical cleavage of the S. aureus agr gene was then added to cause lethality to the bacteria. The CRISPR–dCas9 module targeted the agr P2 and P3 gene to block virulence, creatively transformed PIs into “antibacterial drones” (ABDs) (Figures 7(a) and 7(b)) that prevent S. aureus infections [234]. The results showed that these constructed ABDs performed specific killing activities against several S. aureus and Listeria monocytogenes strains (Figure 7(c)). When mice were injected with a fatal staphylococcus, the genetically modified S. aureus PIs killed the pathogenic bacteria and increased the survival rate of infected mice (Figure 7(d)).

At present, two biological companies (Locus Biosciences and Eligo Biosciences) are developing advanced antibacterial therapies with the CRISPR-Cas system. Unlike CRISPR-Cas9, they use CRISPR-Cas3, because the latter can effectively remove the long segment of DNA at a target position in the genome, which is not easy to be achieved by the traditional CRISPR-Cas9 system [235, 236]. Locus Biosciences further exploited the unique properties of CRISPR-Cas3 to target and irreversibly destroy bacterial DNA to kill target bacteria or eliminate specific bacterial populations [237]. Eligo Bioscience focuses on the usefulness of CRISPR-Cas3, hoping that it will not only successfully kill more and more superbugs but also prevent the emergence of superbugs in the future. Though clinical trial has not been done yet, the company has successfully used CRISPR-Cas3 to cure mice infected with two different E. coli strains [238].

6.2. CRISPR-Responsive Smart Materials

Cas9 is the most in-depth and widely used Cas enzyme thus far and has great application prospects in gene editing and disease treatment [239241]. However, CRISPR-Cas9 lacks an enzyme-active domain that cleaves single-stranded nucleic acids and cannot be used for the detection of pathogenic infection in vitro [242]. In contrast, Cas12a has an additional enzymatic domain, which can be activated to cleave single-stranded substrate ssDNA when recognizing the target gene sequence of a pathogen or tumor. After the domain is being activated, the enzyme will release a fluorescent reporter group that is linked with ssDNA. The latter sequence information can be transformed to a fluorescence signal [243]. This feature has successfully achieved the sensitivity that cannot be achieved by ordinary real-time quantitative PCR and get rid of the dependence on a real-time quantitative PCR instrument as it targets known sequences of pathogens.

English et al. have creatively integrated CRISPR-Cas12a technology into DNA hydrogels (Figure 8) [244]. The Cas12a-gRNA can specifically recognize foreign DNA and activated Cas12a to cleave target dsDNA and proximal indiscriminate ssDNA. Data showed that the DNA hydrogel was gradually disintegrated based on the response to the targeted cleavage of dsDNA and can be used for the controlled release of drugs/antibiotics, nanoparticles, and even cells (Figure 8(a)). The hydrogel structure can respond to any targeted DNA sequence as gRNA within the hydrogel targets genes involved in the antibiotic-resistance mechanisms of S. aureus, such as ermA, ermC, spa, and vanA (Figure 8(b)). The hydrogel system required only nanomolar or even picomolar concentration of targeted DNA to achieve efficient cutting of the CRISPR-Cas12a system (Figure 8(c)) [244]. The authors also reported on the controlled release of small molecule drugs or proteins in multiarm polyethylene glycol hydrogels, gold NPs, and even live-cell controlled release polyacrylamide hydrogels, which subtly convert biological information into macroscopic changes in material properties (Figure 8(d)). This platform shows a potential application value in medical analysis and environmental monitoring and has a promising future in the application of POT.

In summary, though the treatment of antimicrobial agents based on CRISPR-Cas systems still has a long way to go from laboratory to clinical applications, this technical strategy is novel and has great potential for combatting AMR. Once the technique is established, it will change the way we treat MDR infections in patients. Besides that, it also represents a novel and powerful way in catalyzing the change of human microbial composition and helps to develop new treatments for key diseases of drug-resistant bacterial infections.

7. Microbiota Therapy in Combatting AMR

The role of microbiota in regulating human health and disease status has received increasing attention in recent years. The destruction of intestinal flora has been proven to be involved in the pathogenesis of many infectious diseases [245, 246]. Manipulating and engineering human microbiota for combatting AMR are an attractive option for POT.

Recent studies have found that drug resistance is transmitted via gut bacteria even without the use of antibiotics. Persistent bacteria, also known as persisters, are the main culprits for the spread of AMR [247]. Bacteria like Salmonella carry resistance genes, allowing them to survive in antibiotic treatment and remain undetected for months. They are in a temporary dormant state and can minimize their metabolism, preventing the antibiotics from killing them. If the condition favors bacterial survival, dormant Salmonella can transfer their resistance gene to other bacteria of the same species or even to other species such as E. coli in the gut and infection can then reemerge [247]. Fecal microbiota transplantation (FMT) therapy can circumvent the risk of drug resistance caused by antibiotic treatment, which is mainly to rebuild the intestinal tract of the patient by transplanting the intestinal flora from human feces into the intestine of the patient. This therapy can also be used for the treatment of diarrhea, intestinal microflora disorder, and other diseases [248250]. The implication of fecal transplantation is to reestablish a normal intestinal microecosystem. Utilizing the FMT for the treatment of C. difficile colitis is the most in-depth application case for clinical research [251253]. One of the causes of C. difficile colitis is the inappropriate use of broad-spectrum antibiotics, causing damage to the normal intestinal microbiota [254, 255]. A clinical study demonstrated that the initial cure rate reached 91.2%, and the recurrence rate was only 5.5% after 611 patients were treated with FMT, showing that it is a fairly good treatment [256]. It is important to first screen suitable fecal donors before the FMT can be initiated. Fresh feces of healthy donors are obtained and transplanted into patients’ intestines and stomach through patients’ mouth, nose, or anus [257, 258]. Most treatment operations have been performed through enemas at present. The applicability of FMT remains a concern as there are deficiencies in the effectiveness and safety of the methodology. Recently, the US Food and Drug Administration (FDA) reported that a patient died as a result of FMT treatment and warns that there is a serious risk for receiving FMT treatment, which is the spreading of bacteria that are resistant to various drugs [259]. More research is required to address the issues related to FMT and validate the efficacy of the treatment before being expanded to the public.

The use of probiotics to treat various infectious diseases is another alternative of POT. Probiotics play important roles in the fight against pathogens in humans. They mainly inhibit or exclude the growth of other harmful microorganisms by competing for nutrients or adhesion space, releasing antibacterial compounds, stimulating the host immune system, and enhancing the intestinal barrier function [260, 261]. In a study of the effects of probiotics on the incidence of C. difficile-associated diarrhea for children and adults in hospital and outpatient settings, the use of Lactobacillus, Saccharomyces, and a mixture of probiotics significantly reduced the incidence 63.7%, 58.5%, and 58.2%, respectively [262]. A modified strain of E. coli Nissle 1917 has been found to release toxins that selectively eliminated P. aeruginosa [263]. Researchers further engineered this probiotic strain to confer a gene that can disrupt the stability of the P. aeruginosa biofilm (Figures 9(a) and 9(b)). The engineered probiotic strain showed an impressively prophylactic and therapeutic activity against P. aeruginosa in two gut-infected models, mice, and C. elegans (Figures 9(c)9(e)). Engineered probiotics represent a more primitive way to combat against AMR and have shown great potential in preventive and therapeutic activity against intestinal infections [264]. Nevertheless, more investigation or clinical studies are needed to further evaluate and understand the mechanisms involved in fighting against AMR.

In summary, microbiota therapy is an attractive option for the prevention and resolution of AMR. On the one hand, the treatment is not easy to cause drug resistance; on the other hand, it will not destroy the human microbiota or increase the possibility of reinfection. However, the lack of systematic understanding of the complex genome and phylogenetic diversity of human microbiota is a key challenge for this therapy currently. Therefore, it is necessary to have a deeper understanding of the complex role of microbiota in the pathogenesis of specific diseases. In addition, although microbiota therapy has been in the late-stage of clinical trials to prevent CDI recurrence, the manufacturing process of live bacteria products is complex and expensive, and there is still a lack of proven theoretical basis or models to support the search for appropriate doses. All these make microbiota therapy still need to move forward cautiously in the fight against AMR.

8. Concluding Remarks and Future Perspectives

The great success of conventional antibiotics has greatly improved people’s quality of life, but drug resistance poses serious threats to the public health nowadays. Conventional antibacterial treatment faces many limitations, e.g., the treatment regimens available for MDR pathogens are depleted and the available antibiotic-specific activity is lacking. As a result, alternatives to traditional antibiotics are in urgent need, i.e., POT strategies targeting either specific bacterial species or strains or host infection sites, to address the growing clinical embarrassments of available antibiotics. Conjugation of existing antibiotics not only provides conventional antibiotics with dual-targeting and synergistic antibacterial activities to improve their pharmacokinetic parameters but also reduces their sensitivity to degrading enzymes and efflux systems. Despite these advantages, the efficacy of conjugated antibiotics is expected to prove superior to or at least equal to that of combination therapies, and the mechanisms of these conjugates against drug resistance still need to be systematically studied. AMPs are less likely to induce drug resistance compared with conventional antibiotics, but more efforts are required to be done in this research field, especially clinical trials, to evaluate the efficacy and safety of AMPs in fighting against bacteria. mAbs have been approved for the treatment and prevention of some common bacterial infections, but their widespread applications are constrained by production costs, expiration date, and individual differences among patients. NPs have unique advantages in the targeted delivery of antibiotics. Current researches focus on the basic strategy of targeted delivery of NPs. The clinical application of antimicrobial NPs is rare at present, and we foresee that it has a bright future in the treatment of infectious diseases. The CRISPR system has made significant progress in the fight against drug-resistant diseases, but there is still room for improvement for safer and more efficient drug delivery systems. Recent research has also developed new strategies for targeting delivery systems, i.e., toxin-intein antimicrobial that can specifically eliminate pathogenic bacteria without inducing damage on the host’s beneficial microbiome [265]. This is expected to be a new strategy and trend for treating bacteria-related disorders and AMR. A deep understanding of microbial dynamics and metabolic interactions is important for the development of inhibiting or conquering opportunistic pathogens.

Each new therapy has its own advantages and limitations. For example, AACs are chemically synthesized, and their transportation and storage do not require special equipment, so they have advantages over the price of other treatments. But in some ways, this treatment strategy can only slow down the development of drug resistance. For some infected patients who need precision or personalized care, therapies based on antibody or CRISPR system may be the next frontier directions because they have a highly precise targeting effect. However, these two therapies are relatively expensive, antibody-based therapy should avoid antibody enhancement effects, and CRISPR system-based therapy should pay attention to off-target effects. AMPs are generally positively charged cationic peptides with broad-spectrum antibacterial activity. Their molecular weights are between traditional antibiotics and antibodies, and the cost of synthesis is relatively high. Minimizing the degradation and toxic effects on mammalian cells in order to obtain a large enough treatment window remains the main challenge for the use of AMPs. The major obstacles to the clinical application of antimicrobial NPs are their safety and cytotoxicity concerns, such as metabolism, clearance, and mode of action, which must be further evaluated, since the interaction of NPs with cells and tissues is still poorly understood. Another obstacle to overcome is the development of affordable mass manufacturing methods for NPs. In spite of this, they have a bright future in achieving drug delivery at specific infection sites in reducing off-target effects, reducing unnecessary toxicity, and improving the therapeutic efficacy of drugs. Microbiota therapy is an indirect treatment strategy which does not inhibit or kill bacteria but play a role by regulating or interacting with complex microorganisms. Thus, traditional antimicrobial measurements such as MIC assay cannot be used to measure its therapeutic effect. Therefore, finding the evaluation method of the appropriate dose still needs to be explored. In addition, unlike those therapies mentioned above, tailor-made treatments are currently difficult to achieve and may require a comprehensive understanding of the underlying mechanisms and patient factors of the microbiota. Undeniably, these POT strategies cannot completely replace traditional antibiotic therapy but they can act as coadjuvants to fight against AMR. Therefore, therapies based on antibiotics and their combination with AMPs, antibodies, nanotechnology, and CRISPR systems are worth exploring to discover their full potential. Most of these treatment pathways are still under development and requires time, resources, and efforts for the further advancement.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.


This work was financially supported by the National Key R&D Program of China (2018YFC1105402), the National Natural Science Foundation of China (21875189 and 21706222), the Key R&D Program of Jiangsu Province (BE201740), the Innovative Talents Promotion Project of Shaanxi Province (2019KJXX-064), the National Science Basic Research Plan in Shaanxi Province of China (Program No. 2020JQ-148), and the Fundamental Research Funds for the Central Universities.


  1. B. Aslam, W. Wang, M. I. Arshad et al., “Antibiotic resistance: a rundown of a global crisis,” Infection and Drug Resistance, vol. 11, pp. 1645–1658, 2018. View at: Publisher Site | Google Scholar
  2. L. B. Rice, “Antimicrobial resistance in gram-positive bacteria,” American Journal of Infection Control, vol. 34, Supplement, no. 5, pp. S11–S19, 2006. View at: Publisher Site | Google Scholar
  3. M. Anderson, K. Schulze, A. Cassini, D. Plachouras, and E. Mossialos, “A governance framework for development and assessment of national action plans on antimicrobial resistance,” Lancet Infectious Diseases, vol. 19, no. 11, pp. e371–e384, 2019. View at: Publisher Site | Google Scholar
  4. L. S. J. Roope, R. D. Smith, K. B. Pouwels et al., “The challenge of antimicrobial resistance: what economics can contribute,” Science, vol. 364, no. 6435, article eaau4679, 2019. View at: Publisher Site | Google Scholar
  5. K. U. Jansen, C. Knirsch, and A. S. Anderson, “The role of vaccines in preventing bacterial antimicrobial resistance,” Nature Medicine, vol. 24, no. 1, pp. 10–19, 2018. View at: Publisher Site | Google Scholar
  6. M. E. A. de Kraker, A. J. Stewardson, and S. Harbarth, “Will 10 million people die a year due to antimicrobial resistance by 2050?” PLoS Medicine, vol. 13, no. 11, article e1002184, 2016. View at: Publisher Site | Google Scholar
  7. R. E. Hancock, “Mechanisms of action of newer antibiotics for Gram-positive pathogens,” The Lancet Infectious Diseases, vol. 5, no. 4, pp. 209–218, 2005. View at: Publisher Site | Google Scholar
  8. E. Tacconelli, E. Carrara, A. Savoldi et al., “Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis,” The Lancet Infectious Diseases, vol. 18, no. 3, pp. 318–327, 2018. View at: Publisher Site | Google Scholar
  9. M. Ferri, E. Ranucci, P. Romagnoli, and V. Giaccone, “Antimicrobial resistance: a global emerging threat to public health systems,” Critical Reviews in Food Science and Nutrition, vol. 57, no. 13, pp. 2857–2876, 2015. View at: Publisher Site | Google Scholar
  10. L. Di and E. H. Kerns, Drug-like properties: concepts, structure design and methods from ADME to toxicity optimization, Academic press, 2015.
  11. M. Zhou, R.-H. Zhang, M. Wang, G.-B. Xu, and S.-G. Liao, “Prodrugs of triterpenoids and their derivatives,” European Journal of Medicinal Chemistry, vol. 131, pp. 222–236, 2017. View at: Publisher Site | Google Scholar
  12. U. Theuretzbacher, “Accelerating resistance, inadequate antibacterial drug pipelines and international responses,” International Journal of Antimicrobial Agents, vol. 39, no. 4, pp. 295–299, 2012. View at: Publisher Site | Google Scholar
  13. O. Cars, A. Hedin, and A. Heddini, “The global need for effective antibiotics—moving towards concerted action,” Drug Resistance Updates, vol. 14, no. 2, pp. 68-69, 2011. View at: Publisher Site | Google Scholar
  14. P. Fernandes and E. Martens, “Antibiotics in late clinical development,” Biochemical Pharmacology, vol. 133, pp. 152–163, 2017. View at: Publisher Site | Google Scholar
  15. L. Freire-Moran, B. Aronsson, C. Manz et al., “Critical shortage of new antibiotics in development against multidrug-resistant bacteria-time to react is now,” Drug Resistance Updates, vol. 14, no. 2, pp. 118–124, 2011. View at: Publisher Site | Google Scholar
  16. M. Hay, D. W. Thomas, J. L. Craighead, C. Economides, and J. Rosenthal, “Clinical development success rates for investigational drugs,” Nature Biotechnology, vol. 32, no. 1, pp. 40–51, 2014. View at: Publisher Site | Google Scholar
  17. The Pew Charitable Trusts, “Antibiotics currently in global clinical development,” September 2019, View at: Google Scholar
  18. S. Nomura, H. Hanaki, and A. Nagayama, “Tazobactam-piperacillin compared with sulbactam-ampicillin, clavulanic acid-ticarcillin, sulbactam-cefoperazone, and piperacillin for activity against beta-lactamase-producing bacteria isolated from patients with complicated urinary tract infections,” Journal of Chemotherapy, vol. 9, no. 2, pp. 89–94, 2013. View at: Publisher Site | Google Scholar
  19. T. P. Lodise Jr., B. Lomaestro, and G. L. Drusano, “Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy,” Clinical Infectious Diseases, vol. 44, no. 3, pp. 357–363, 2007. View at: Publisher Site | Google Scholar
  20. L. A. Petty, O. Henig, T. S. Patel, J. M. Pogue, and K. S. Kaye, “Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae,” Infection and Drug Resistance, vol. 11, pp. 1461–1472, 2018. View at: Publisher Site | Google Scholar
  21. G. G. Zhanel, C. D. Lawson, H. Adam et al., “Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination,” Drugs, vol. 73, no. 2, pp. 159–177, 2013. View at: Publisher Site | Google Scholar
  22. E. J. Zasowski, J. M. Rybak, and M. J. Rybak, “The β-lactams strike back: ceftazidime-avibactam,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, vol. 35, no. 8, pp. 755–770, 2015. View at: Publisher Site | Google Scholar
  23. P. Klahn and M. Bronstrup, “Bifunctional antimicrobial conjugates and hybrid antimicrobials,” Natural Product Reports, vol. 34, no. 7, pp. 832–885, 2017. View at: Publisher Site | Google Scholar
  24. V. Pokrovskaya and T. Baasov, “Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance,” Expert Opinion on Drug Discovery, vol. 5, no. 9, pp. 883–902, 2010. View at: Publisher Site | Google Scholar
  25. H. Brötz-Oesterhelt and N. A. Brunner, “How many modes of action should an antibiotic have?” Current Opinion in Pharmacology, vol. 8, no. 5, pp. 564–573, 2008. View at: Publisher Site | Google Scholar
  26. S. Shapiro, “Speculative strategies for new antibacterials: all roads should not lead to Rome,” The Journal of Antibiotics, vol. 66, no. 7, pp. 371–386, 2013. View at: Publisher Site | Google Scholar
  27. M.-U. Rashid, A. Dalhoff, A. Weintraub, and C. E. Nord, “In vitro activity of MCB3681 against Clostridium difficile strains,” Anaerobe, vol. 28, pp. 216–219, 2014. View at: Publisher Site | Google Scholar
  28. D. Baldoni, M. Gutierrez, W. Timmer, and J. Dingemanse, “Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses,” Journal of Antimicrobial Chemotherapy, vol. 69, no. 3, pp. 706–714, 2014. View at: Publisher Site | Google Scholar
  29. A. Kali, M. V. P. Charles, and S. Srirangaraj, “Cadazolid: a new hope in the treatment of Clostridium difficile infection,” The Australasian Medical Journal, vol. 8, no. 8, pp. 253–262, 2015. View at: Publisher Site | Google Scholar
  30. H. H. Locher, P. Seiler, X. Chen et al., “In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 2, pp. 892–900, 2014. View at: Publisher Site | Google Scholar
  31. G. T. Robertson, E. J. Bonventre, T. B. Doyle et al., “In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with Staphylococci and Streptococci,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 7, pp. 2324–2334, 2008. View at: Publisher Site | Google Scholar
  32. G. T. Robertson, E. J. Bonventre, T. B. Doyle et al., “In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 7, pp. 2313–2323, 2008. View at: Publisher Site | Google Scholar
  33. V. Pokrovskaya, V. Belakhov, M. Hainrichson, S. Yaron, and T. Baasov, “Design, synthesis, and evaluation of novel fluoroquinolone−aminoglycoside hybrid antibiotics,” Journal of Medicinal Chemistry, vol. 52, no. 8, pp. 2243–2254, 2009. View at: Publisher Site | Google Scholar
  34. B. K. Gorityala, G. Guchhait, S. Goswami et al., “Hybrid antibiotic overcomes resistance in P. aeruginosa by enhancing outer membrane penetration and reducing efflux,” Journal of Medicinal Chemistry, vol. 59, no. 18, pp. 8441–8455, 2016. View at: Publisher Site | Google Scholar
  35. K. Poole, “Aminoglycoside resistance in Pseudomonas aeruginosa,” Antimicrobial Agents and Chemotherapy, vol. 49, no. 2, pp. 479–487, 2005. View at: Publisher Site | Google Scholar
  36. J. P. Maianti and S. Hanessian, “Structural hybridization of three aminoglycoside antibiotics yields a potent broad-spectrum bactericide that eludes bacterial resistance enzymes,” Medchemcomm, vol. 7, no. 1, pp. 170–176, 2016. View at: Publisher Site | Google Scholar
  37. S. Hanessian, J. P. Maianti, R. D. Matias, L. A. Feeney, and E. S. Armstrong, “Hybrid aminoglycoside antibiotics via tsuji palladium-catalyzed allylic deoxygenation,” Organic Letters, vol. 13, no. 24, pp. 6476–6479, 2011. View at: Publisher Site | Google Scholar
  38. J. S. Bradley, H. Broadhurst, K. Cheng et al., “Safety and efficacy of ceftazidime-avibactam plus metronidazole in the treatment of children ≥3 months to <18 years with complicated intra-abdominal Infection,” The Pediatric Infectious Disease Journal, vol. 38, no. 8, pp. 816–824, 2019. View at: Publisher Site | Google Scholar
  39. S. Dhillon, “Meropenem/vaborbactam: a review in complicated urinary tract infections,” Drugs, vol. 78, no. 12, pp. 1259–1270, 2018. View at: Publisher Site | Google Scholar
  40. G. Wu and E. Cheon, “Meropenem-vaborbactam for the treatment of complicated urinary tract infections including acute pyelonephritis,” Expert Opinion on Pharmacotherapy, vol. 19, no. 13, pp. 1495–1502, 2018. View at: Publisher Site | Google Scholar
  41. P. Bhagunde, P. Patel, M. Lala et al., “Population pharmacokinetic analysis for imipenem–relebactam in healthy volunteers and patients with bacterial infections,” CPT: Pharmacometrics & Systems Pharmacology, vol. 8, no. 10, pp. 748–758, 2019. View at: Publisher Site | Google Scholar
  42. K. Young, R. E. Painter, S. L. Raghoobar et al., “In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa,” BMC Microbiology, vol. 19, no. 1, p. 150, 2019. View at: Publisher Site | Google Scholar
  43. M. Bukvić Krajačić, P. Novak, M. Cindrić, K. Brajša, M. Dumić, and N. Kujundžić, “Azithromycin–sulfonamide conjugates as inhibitors of resistant Streptococcus pyogenes strains,” European Journal of Medicinal Chemistry, vol. 42, no. 2, pp. 138–145, 2007. View at: Publisher Site | Google Scholar
  44. A. Hutinec, M. Đerek, G. Lazarevski et al., “Novel 8a-aza-8a-homoerythromycin—4 -(3-substituted-amino) propionates with broad spectrum antibacterial activity,” Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 11, pp. 3244–3249, 2010. View at: Publisher Site | Google Scholar
  45. P. C. Appelbaum and P. A. Hunter, “The fluoroquinolone antibacterials: past, present and future perspectives,” International Journal of Antimicrobial Agents, vol. 16, no. 1, pp. 5–15, 2000. View at: Publisher Site | Google Scholar
  46. V. T. Andriole, “The quinolones: past, present, and future,” Clinical Infectious Diseases, vol. 41, Supplement_2, pp. S113–S119, 2005. View at: Publisher Site | Google Scholar
  47. J. M. Blondeau, “Fluoroquinolones: mechanism of action, classification, and development of resistance,” Survey of Ophthalmology, vol. 49, Supplement 2, no. 2, pp. S73–S78, 2004. View at: Publisher Site | Google Scholar
  48. B. Bozdogan and P. C. Appelbaum, “Oxazolidinones: activity, mode of action, and mechanism of resistance,” International Journal of Antimicrobial Agents, vol. 23, no. 2, pp. 113–119, 2004. View at: Publisher Site | Google Scholar
  49. O. A. Phillips and L. H. Sharaf, “Oxazolidinone antimicrobials: a patent review (2012-2015),” Expert Opinion on Therapeutic Patents, vol. 26, no. 5, pp. 591–605, 2016. View at: Publisher Site | Google Scholar
  50. D. J. Diekema and R. N. Jones, “Oxazolidinone antibiotics,” The Lancet, vol. 358, no. 9297, pp. 1975–1982, 2001. View at: Publisher Site | Google Scholar
  51. L. L. Silver and K. A. Bostian, “Discovery and development of new antibiotics: the problem of antibiotic resistance,” Antimicrobial Agents and Chemotherapy, vol. 37, no. 3, pp. 377–383, 1993. View at: Publisher Site | Google Scholar
  52. M. R. Barbachyn, “Oxazolidinone antibacterial agents,” in Antibiotic Discovery and Development, T. J. Dougherty and M. J. Pucci, Eds., pp. 271–299, Springer US, Boston, MA, 2012. View at: Publisher Site | Google Scholar
  53. B. T. Endres, E. Bassères, M. J. Alam, and K. W. Garey, “Cadazolid for the treatment of Clostridium difficile,” Expert Opinion on Investigational Drugs, vol. 26, no. 4, pp. 509–514, 2017. View at: Publisher Site | Google Scholar
  54. H. H. Locher, P. Caspers, T. Bruyère et al., “Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 2, pp. 901–908, 2014. View at: Publisher Site | Google Scholar
  55. J. L. Houghton, K. D. Green, W. Chen, and S. Garneau-Tsodikova, “The future of aminoglycosides: the end or renaissance?” Chembiochem, vol. 11, no. 7, pp. 880–902, 2010. View at: Publisher Site | Google Scholar
  56. M.-P. Mingeot-Leclercq, Y. Glupczynski, and P. M. Tulkens, “Aminoglycosides: activity and resistance,” Antimicrobial Agents and Chemotherapy, vol. 43, no. 4, pp. 727–737, 1999. View at: Publisher Site | Google Scholar
  57. P. Dozzo and H. E. Moser, “New aminoglycoside antibiotics,” Expert Opinion on Therapeutic Patents, vol. 20, no. 10, pp. 1321–1341, 2010. View at: Publisher Site | Google Scholar
  58. B. Becker and M. A. Cooper, “Aminoglycoside antibiotics in the 21st century,” ACS Chemical Biology, vol. 8, no. 1, pp. 105–115, 2013. View at: Publisher Site | Google Scholar
  59. K. M. Krause, A. W. Serio, T. R. Kane, and L. E. Connolly, “Aminoglycosides: an overview,” Cold Spring Harbor Perspectives in Medicine, vol. 6, no. 6, article a027029, 2016. View at: Publisher Site | Google Scholar
  60. L. P. Kotra, J. Haddad, and S. Mobashery, “Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 12, pp. 3249–3256, 2000. View at: Publisher Site | Google Scholar
  61. S. Jana and J. K. Deb, “Molecular understanding of aminoglycoside action and resistance,” Applied Microbiology and Biotechnology, vol. 70, no. 2, pp. 140–150, 2006. View at: Publisher Site | Google Scholar
  62. H. W. Taber, J. P. Mueller, P. F. Miller, and A. S. Arrow, “Bacterial uptake of aminoglycoside antibiotics,” Microbiological Reviews, vol. 51, no. 4, pp. 439–457, 1987. View at: Publisher Site | Google Scholar
  63. Y. Doi and Y. Arakawa, “16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides,” Clinical Infectious Diseases, vol. 45, no. 1, pp. 88–94, 2007. View at: Publisher Site | Google Scholar
  64. P. Levasseur, A.-M. Girard, M. Claudon et al., “In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates,” Antimicrobial Agents and Chemotherapy, vol. 56, no. 3, pp. 1606–1608, 2012. View at: Publisher Site | Google Scholar
  65. M. A. Hackel, O. Lomovskaya, M. N. Dudley, J. A. Karlowsky, and D. F. Sahm, “In vitro activity of meropenem-vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae,” Antimicrobial Agents and Chemotherapy, vol. 62, no. 1, pp. e01904–e01917, 2018. View at: Publisher Site | Google Scholar
  66. D. Sun, D. Rubio-Aparicio, K. Nelson, M. N. Dudley, and O. Lomovskaya, “Meropenem-vaborbactam resistance selection, resistance prevention, and molecular mechanisms in mutants of KPC-producing Klebsiella pneumoniae,” Antimicrobial Agents and Chemotherapy, vol. 61, no. 12, article e01694, 2017. View at: Publisher Site | Google Scholar
  67. G. G. Zhanel, C. K. Lawrence, H. Adam et al., “Imipenem–relebactam and meropenem–vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations,” Drugs, vol. 78, no. 1, pp. 65–98, 2018. View at: Publisher Site | Google Scholar
  68. J. A. Karlowsky, S. H. Lob, K. M. Kazmierczak, K. Young, M. R. Motyl, and D. F. Sahm, “In VitroActivity of imipenem-relebactam against clinical isolates of gram-negative Bacilli isolated in hospital laboratories in the United States as part of the SMART 2016 Program,” Antimicrobial Agents and Chemotherapy, vol. 62, no. 7, article e00169, 2018. View at: Publisher Site | Google Scholar
  69. M. Shirley, “Ceftazidime-avibactam: a review in the treatment of serious gram-negative bacterial infections,” Drugs, vol. 78, no. 6, pp. 675–692, 2018. View at: Publisher Site | Google Scholar
  70. S. J. Hecker, K. R. Reddy, M. Totrov et al., “Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX 7009) with utility vs class A serine carbapenemases,” Journal of Medicinal Chemistry, vol. 58, no. 9, pp. 3682–3692, 2015. View at: Publisher Site | Google Scholar
  71. D. C. Griffith, J. S. Loutit, E. E. Morgan, S. Durso, and M. N. Dudley, “Phase 1 study of the safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor vaborbactam (RPX 7009) in healthy adult subjects,” Antimicrobial Agents and Chemotherapy, vol. 60, no. 10, pp. 6326–6332, 2016. View at: Publisher Site | Google Scholar
  72. S. C. J. Jorgensen and M. J. Rybak, “Meropenem and vaborbactam: stepping up the battle against carbapenem-resistant Enterobacteriaceae,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, vol. 38, no. 4, pp. 444–461, 2018. View at: Publisher Site | Google Scholar
  73. O. Lomovskaya, D. Sun, D. Rubio-Aparicio et al., “Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae,” Antimicrobial Agents and Chemotherapy, vol. 61, no. 11, article e01443, 2017. View at: Publisher Site | Google Scholar
  74. S. H. Lob, M. A. Hackel, K. M. Kazmierczak et al., “In vitro activity of imipenem-relebactam against gram-negative bacilli isolated from patients with lower respiratory tract infections in the United States in 2015 – results from the SMART global surveillance program,” Diagnostic Microbiology and Infectious Disease, vol. 88, no. 2, pp. 171–176, 2017. View at: Publisher Site | Google Scholar
  75. A. Lapuebla, M. Abdallah, O. Olafisoye et al., “Activity of imipenem with relebactam against gram-negative pathogens from New York City,” Antimicrobial Agents and Chemotherapy, vol. 59, no. 8, pp. 5029–5031, 2015. View at: Publisher Site | Google Scholar
  76. D. M. Livermore, M. Warner, and S. Mushtaq, “Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa,” Journal of Antimicrobial Chemotherapy, vol. 68, no. 10, pp. 2286–2290, 2013. View at: Publisher Site | Google Scholar
  77. T. Mazzei, E. Mini, A. Novelli, and P. Periti, “Chemistry and mode of action of macrolides,” Journal of Antimicrobial Chemotherapy, vol. 31, Supplement_C, pp. 1–9, 1993. View at: Publisher Site | Google Scholar
  78. T. Kuriyama, T. Karasawa, and D. W. Williams, “Chapter thirteen-antimicrobial chemotherapy: significance to healthcare,” in Biofilms in Infection Prevention and Control, S. L. Percival, D. W. Williams, J. Randle, and T. Cooper, Eds., pp. 209–244, Academic Press, Boston, 2014. View at: Google Scholar
  79. W. Schönfeld and S. Mutak, “Azithromycin and novel azalides,” in Macrolide Antibiotics, W. Schönfeld and H. A. Kirst, Eds., pp. 73–95, Birkhäuser Basel, Basel, 2002. View at: Publisher Site | Google Scholar
  80. M. J. Parnham, V. E. Haber, E. J. Giamarellos-Bourboulis, G. Perletti, G. M. Verleden, and R. Vos, “Azithromycin: mechanisms of action and their relevance for clinical applications,” Pharmacology & Therapeutics, vol. 143, no. 2, pp. 225–245, 2014. View at: Publisher Site | Google Scholar
  81. J. M. Zuckerman, F. Qamar, and B. R. Bono, “Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline),” Medical Clinics of North America, vol. 95, no. 4, pp. 761–791, 2011. View at: Publisher Site | Google Scholar
  82. J. M. Zuckerman, “Macrolides and ketolides: azithromycin, clarithromycin, telithromycin,” Infectious Disease Clinics of North America, vol. 18, no. 3, pp. 621–649, 2004. View at: Publisher Site | Google Scholar
  83. J. Molina-Infante and J. P. Gisbert, “Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance,” World Journal of Gastroenterology, vol. 20, no. 30, pp. 10338–10347, 2014. View at: Publisher Site | Google Scholar
  84. J. Cruz, C. Ortiz, F. Guzmán, R. Fernández-Lafuente, and R. Torres, “Antimicrobial peptides: promising compounds against pathogenic microorganisms,” Current Medicinal Chemistry, vol. 21, no. 20, pp. 2299–2321, 2014. View at: Publisher Site | Google Scholar
  85. S.-J. Kang, S. J. Park, T. Mishig-Ochir, and B.-J. Lee, “Antimicrobial peptides: therapeutic potentials,” Expert Review of Anti-Infective Therapy, vol. 12, no. 12, pp. 1477–1486, 2014. View at: Publisher Site | Google Scholar
  86. C. Adessi and C. Soto, “Converting a peptide into a drug: strategies to improve stability and bioavailability,” Current Medicinal Chemistry, vol. 9, no. 9, pp. 963–978, 2002. View at: Publisher Site | Google Scholar
  87. R. Eckert, “Road to clinical efficacy: challenges and novel strategies for antimicrobial peptide development,” Future Microbiology, vol. 6, no. 6, pp. 635–651, 2011. View at: Publisher Site | Google Scholar
  88. L. Di, “Strategic approaches to optimizing peptide ADME properties,” The AAPS Journal, vol. 17, no. 1, pp. 134–143, 2015. View at: Publisher Site | Google Scholar
  89. R. Saravanan, X. Li, K. Lim et al., “Design of short membrane selective antimicrobial peptides containing tryptophan and arginine residues for improved activity, salt-resistance, and biocompatibility,” Biotechnology and Bioengineering, vol. 111, no. 1, pp. 37–49, 2014. View at: Publisher Site | Google Scholar
  90. C. Zhou, X. Qi, P. Li et al., “High potency and broad-spectrum antimicrobial peptides synthesized via ring-opening polymerization of α-aminoacid-N-carboxyanhydrides,” Biomacromolecules, vol. 11, no. 1, pp. 60–67, 2010. View at: Publisher Site | Google Scholar
  91. J. F. Marcos and M. Gandía, “Antimicrobial peptides: to membranes and beyond,” Expert Opinion on Drug Discovery, vol. 4, no. 6, pp. 659–671, 2009. View at: Publisher Site | Google Scholar
  92. C.-F. Le, C.-M. Fang, and S. D. Sekaran, “Intracellular targeting mechanisms by antimicrobial peptides,” Antimicrobial Agents and Chemotherapy, vol. 61, no. 4, article e02340, 2017. View at: Publisher Site | Google Scholar
  93. M. N. Melo, R. Ferre, and M. A. R. B. Castanho, “Antimicrobial peptides: linking partition, activity and high membrane-bound concentrations,” Nature Reviews Microbiology, vol. 7, no. 3, pp. 245–250, 2009. View at: Publisher Site | Google Scholar
  94. C. Lang and C. Staiger, “Tyrothricin–an underrated agent for the treatment of bacterial skin infections and superficial wounds?” Die Pharmazie-An International Journal of Pharmaceutical Sciences, vol. 71, no. 6, pp. 299–305, 2016. View at: Google Scholar
  95. R. J. Dubos and C. Cattaneo, “Studies on a bactericidal agent extracted from a soil Bacillus: III. Preparation and activity of a protein-free fraction,” The Journal of Experimental Medicine, vol. 70, no. 3, pp. 249–256, 1939. View at: Publisher Site | Google Scholar
  96. K. Matsuzaki, O. Murase, N. Fujii, and K. Miyajima, “An antimicrobial peptide, magainin 2, induced rapid flip-flop of phospholipids coupled with pore formation and peptide translocation,” Biochemistry, vol. 35, no. 35, pp. 11361–11368, 1996. View at: Publisher Site | Google Scholar
  97. J. Overhage, A. Campisano, M. Bains, E. C. W. Torfs, B. H. A. Rehm, and R. E. W. Hancock, “Human host defense peptide LL-37 prevents bacterial biofilm formation,” Infection and Immunity, vol. 76, no. 9, pp. 4176–4182, 2008. View at: Publisher Site | Google Scholar
  98. D. Vandamme, B. Landuyt, W. Luyten, and L. Schoofs, “A comprehensive summary of LL-37, the factotum human cathelicidin peptide,” Cellular Immunology, vol. 280, no. 1, pp. 22–35, 2012. View at: Publisher Site | Google Scholar
  99. M. F. Nilsson, B. Sandstedt, O. Sørensen, G. Weber, N. Borregaard, and M. Ståhle-Bäckdahl, “The human cationic antimicrobial protein (hCAP18), a peptide antibiotic, is widely expressed in human squamous epithelia and colocalizes with interleukin-6,” Infection and Immunity, vol. 67, no. 5, pp. 2561–2566, 1999. View at: Publisher Site | Google Scholar
  100. J.-M. Schröder and J. Harder, “Human beta-defensin-2,” The International Journal of Biochemistry & Cell Biology, vol. 31, no. 6, pp. 645–651, 1999. View at: Publisher Site | Google Scholar
  101. D. A. Steinberg, M. A. Hurst, C. A. Fujii et al., “Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity,” Antimicrobial Agents and Chemotherapy, vol. 41, no. 8, pp. 1738–1742, 1997. View at: Publisher Site | Google Scholar
  102. T. Nakamura, H. Furunaka, T. Miyata et al., “Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure,” Journal of Biological Chemistry, vol. 263, no. 32, pp. 16709–16713, 1988. View at: Google Scholar
  103. M. E. Selsted, M. J. Novotny, W. L. Morris, Y.-Q. Tang, W. Smith, and J. S. Cullor, “Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils,” Journal of Biological Chemistry, vol. 267, no. 7, pp. 4292–4295, 1992. View at: Google Scholar
  104. M. Wu and R. E. W. Hancock, “Interaction of the cyclic antimicrobial cationic peptide bactenecin with the outer and cytoplasmic membrane,” Journal of Biological Chemistry, vol. 274, no. 1, pp. 29–35, 1999. View at: Publisher Site | Google Scholar
  105. M. Mahlapuu, J. Hakansson, L. Ringstad, and C. Bjorn, “Antimicrobial peptides: an emerging category of therapeutic agents,” Frontiers in Cellular and Infection Microbiology, vol. 6, p. 194, 2016. View at: Publisher Site | Google Scholar
  106. P. Vlieghe, V. Lisowski, J. Martinez, and M. Khrestchatisky, “Synthetic therapeutic peptides: science and market,” Drug Discovery Today, vol. 15, no. 1-2, pp. 40–56, 2010. View at: Publisher Site | Google Scholar
  107. Y.-Q. Tang, J. Yuan, G. Ösapay et al., “A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins,” Science, vol. 286, no. 5439, pp. 498–502, 1999. View at: Publisher Site | Google Scholar
  108. L. Y. Chan, V. M. Zhang, Y. H. Huang et al., “Cyclization of the antimicrobial peptide gomesin with native chemical ligation: influences on stability and bioactivity,” Chembiochem, vol. 14, no. 5, pp. 617–624, 2013. View at: Publisher Site | Google Scholar
  109. M. Dathe, H. Nikolenko, J. Klose, and M. Bienert, “Cyclization increases the antimicrobial activity and selectivity of arginine-and tryptophan-containing hexapeptides,” Biochemistry, vol. 43, no. 28, pp. 9140–9150, 2004. View at: Publisher Site | Google Scholar
  110. K. Hamamoto, Y. Kida, Y. Zhang, T. Shimizu, and K. Kuwano, “Antimicrobial activity and stability to proteolysis of small linear cationic peptides with D-amino acid substitutions,” Microbiology and Immunology, vol. 46, no. 11, pp. 741–749, 2002. View at: Publisher Site | Google Scholar
  111. M. Wenzel, A. I. Chiriac, A. Otto et al., “Small cationic antimicrobial peptides delocalize peripheral membrane proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 14, pp. E1409–E1418, 2014. View at: Publisher Site | Google Scholar
  112. T. Baumann, J. H. Nickling, M. Bartholomae, A. Buivydas, O. P. Kuipers, and N. Budisa, “Prospects of in vivo incorporation of non-canonical amino acids for the chemical diversification of antimicrobial peptides,” Frontiers in Microbiology, vol. 8, p. 124, 2017. View at: Publisher Site | Google Scholar
  113. A. Falanga, L. Lombardi, G. Franci et al., “Marine antimicrobial peptides: nature provides templates for the design of novel compounds against pathogenic bacteria,” International Journal of Molecular Sciences, vol. 17, no. 5, p. 785, 2016. View at: Publisher Site | Google Scholar
  114. A. Henninot, J. C. Collins, and J. M. Nuss, “The current state of peptide drug discovery: back to the future?” Journal of Medicinal Chemistry, vol. 61, no. 4, pp. 1382–1414, 2018. View at: Publisher Site | Google Scholar
  115. M. Malmsten, G. Kasetty, M. Pasupuleti, J. Alenfall, and A. Schmidtchen, “Highly selective end-tagged antimicrobial peptides derived from PRELP,” PLoS One, vol. 6, no. 1, article e16400, 2011. View at: Publisher Site | Google Scholar
  116. H. Kato, K. Tsuji, and K.-i. Harada, “Microbial degradation of cyclic peptides produced by bacteria,” The Journal of Antibiotics, vol. 62, no. 4, pp. 181–190, 2009. View at: Publisher Site | Google Scholar
  117. B. Wagner, D. Schumann, U. Linne, U. Koert, and M. A. Marahiel, “Rational design of bacitracin A derivatives by incorporating natural product derived heterocycles,” Journal of the American Chemical Society, vol. 128, no. 32, pp. 10513–10520, 2006. View at: Publisher Site | Google Scholar
  118. I. Kempf, E. Jouy, and C. Chauvin, “Colistin use and colistin resistance in bacteria from animals,” International Journal of Antimicrobial Agents, vol. 48, no. 6, pp. 598–606, 2016. View at: Publisher Site | Google Scholar
  119. E. A. Azzopardi, E. L. Ferguson, and D. W. Thomas, “Colistin past and future: a bibliographic analysis,” Journal of Critical Care, vol. 28, no. 2, pp. 219.e13–219.e19, 2013. View at: Publisher Site | Google Scholar
  120. T. Mogi and K. Kita, “Gramicidin S and polymyxins: the revival of cationic cyclic peptide antibiotics,” Cellular and Molecular Life Sciences, vol. 66, no. 23, pp. 3821–3826, 2009. View at: Publisher Site | Google Scholar
  121. A. P. Zavascki, L. Z. Goldani, J. Li, and R. L. Nation, “Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review,” Journal of Antimicrobial Chemotherapy, vol. 60, no. 6, pp. 1206–1215, 2007. View at: Publisher Site | Google Scholar
  122. F. Rabanal and Y. Cajal, “Recent advances and perspectives in the design and development of polymyxins,” Natural Product Reports, vol. 34, no. 7, pp. 886–908, 2017. View at: Publisher Site | Google Scholar
  123. S. H. Joo, “Cyclic peptides as therapeutic agents and biochemical tools,” Biomolecules & Therapeutics, vol. 20, no. 1, pp. 19–26, 2012. View at: Publisher Site | Google Scholar
  124. M. H. Cardoso, E. S. Cândido, K. G. N. Oshiro, S. B. Rezende, and O. L. Franco, “5- Peptides containing d-amino acids and retro-inverso peptides: general applications and special focus on antimicrobial peptides,” in Peptide Applications in Biomedicine, Biotechnology and Bioengineering, S. Koutsopoulos, Ed., pp. 131–155, Woodhead Publishing, 2018. View at: Google Scholar
  125. D. Nichols, N. Cahoon, E. M. Trakhtenberg et al., “Use of ichip for high-throughput in situ cultivation of “uncultivable” microbial species,” Applied and Environmental Microbiology, vol. 76, no. 8, pp. 2445–2450, 2010. View at: Publisher Site | Google Scholar
  126. L. L. Ling, T. Schneider, A. J. Peoples et al., “A new antibiotic kills pathogens without detectable resistance,” Nature, vol. 517, no. 7535, pp. 455–459, 2015. View at: Publisher Site | Google Scholar
  127. Y. Imai, K. J. Meyer, A. Iinishi et al., “A new antibiotic selectively kills Gram-negative pathogens,” Nature, vol. 576, no. 7787, pp. 459–464, 2019. View at: Publisher Site | Google Scholar
  128. A. Luther, M. Urfer, M. Zahn et al., “Chimeric peptidomimetic antibiotics against Gram-negative bacteria,” Nature, vol. 576, no. 7787, pp. 452–458, 2019. View at: Publisher Site | Google Scholar
  129. X. Q. Yu and M. R. Kanost, “Binding of hemolin to bacterial lipopolysaccharide and lipoteichoic acid: an immunoglobulin superfamily member from insects as a pattern-recognition receptor,” European Journal of Biochemistry, vol. 269, no. 7, pp. 1827–1834, 2002. View at: Publisher Site | Google Scholar
  130. X.-J. Rao and X.-Q. Yu, “Lipoteichoic acid and lipopolysaccharide can activate antimicrobial peptide expression in the tobacco hornworm Manduca sexta,” Developmental & Comparative Immunology, vol. 34, no. 10, pp. 1119–1128, 2010. View at: Publisher Site | Google Scholar
  131. M. Zorko and R. Jerala, “Alexidine and chlorhexidine bind to lipopolysaccharide and lipoteichoic acid and prevent cell activation by antibiotics,” Journal of Antimicrobial Chemotherapy, vol. 62, no. 4, pp. 730–737, 2008. View at: Publisher Site | Google Scholar
  132. S. Choi, A. Isaacs, D. Clements et al., “De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 17, pp. 6968–6973, 2009. View at: Publisher Site | Google Scholar
  133. N. Papo and Y. Shai, “Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes?” Peptides, vol. 24, no. 11, pp. 1693–1703, 2003. View at: Publisher Site | Google Scholar
  134. M. Mazel, P. Clair, C. Rousselle et al., “Doxorubicin-peptide conjugates overcome multidrug resistance,” Anti-Cancer Drugs, vol. 12, no. 2, pp. 107–116, 2001. View at: Publisher Site | Google Scholar
  135. S. A. Onaizi and S. S. J. Leong, “Tethering antimicrobial peptides: current status and potential challenges,” Biotechnology Advances, vol. 29, no. 1, pp. 67–74, 2011. View at: Publisher Site | Google Scholar
  136. D. Marion, M. Zasloff, and A. Bax, “A two-dimensional NMR study of the antimicrobial peptide magainin 2,” FEBS Letters, vol. 227, no. 1, pp. 21–26, 1988. View at: Publisher Site | Google Scholar
  137. K. Matsuzaki, K.-i. Sugishita, M. Harada, N. Fujii, and K. Miyajima, “Interactions of an antimicrobial peptide, magainin 2, with outer and inner membranes of Gram-negative bacteria,” Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1327, no. 1, pp. 119–130, 1997. View at: Publisher Site | Google Scholar
  138. S. Ludtke, K. He, and H. Huang, “Membrane thinning caused by magainin 2,” Biochemistry, vol. 34, no. 51, pp. 16764–16769, 1995. View at: Publisher Site | Google Scholar
  139. C. J. Arnusch, R. J. Pieters, and E. Breukink, “Enhanced membrane pore formation through high-affinity targeted antimicrobial peptides,” PLoS One, vol. 7, no. 6, article e39768, 2012. View at: Publisher Site | Google Scholar
  140. F. Ceccherini, C. Falciani, M. Onori et al., “Antimicrobial activity of levofloxacin–M33 peptide conjugation or combination,” Medchemcomm, vol. 7, no. 2, pp. 258–262, 2016. View at: Publisher Site | Google Scholar
  141. A. Pini, C. Falciani, E. Mantengoli et al., “A novel tetrabranched antimicrobial peptide that neutralizes bacterial lipopolysaccharide and prevents septic shockin vivo,” The FASEB Journal, vol. 24, no. 4, pp. 1015–1022, 2009. View at: Publisher Site | Google Scholar
  142. D. J. Schibli, R. F. Epand, H. J. Vogel, and R. M. Epand, “Tryptophan-rich antimicrobial peptides: comparative properties and membrane interactions,” Biochemistry and Cell Biology, vol. 80, no. 5, pp. 667–677, 2002. View at: Publisher Site | Google Scholar
  143. Y. Shai, “From innate immunity to de-novo designed antimicrobial peptides,” Current Pharmaceutical Design, vol. 8, no. 9, pp. 715–725, 2002. View at: Publisher Site | Google Scholar
  144. K. S. Rao and V. Labhasetwar, “Trans-activating transcriptional activator (TAT) peptide-mediated brain drug delivery,” Journal of Biomedical Nanotechnology, vol. 2, no. 3, pp. 173–185, 2006. View at: Publisher Site | Google Scholar
  145. K. A. Ghaffar, W. M. Hussein, Z. G. Khalil, R. J. Capon, M. Skwarczynski, and I. Toth, “Levofloxacin and indolicidin for combination antimicrobial therapy,” Current Drug Delivery, vol. 12, no. 1, pp. 108–114, 2015. View at: Publisher Site | Google Scholar
  146. B. U. Samuel, B. Hearn, D. Mack et al., “Delivery of antimicrobials into parasites,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 24, pp. 14281–14286, 2011. View at: Publisher Site | Google Scholar
  147. N. W. Schmidt, S. Deshayes, S. Hawker, A. Blacker, A. M. Kasko, and G. C. L. Wong, “Engineering persister-specific antibiotics with synergistic antimicrobial functions,” ACS Nano, vol. 8, no. 9, pp. 8786–8793, 2014. View at: Publisher Site | Google Scholar
  148. A. M. Hansen, G. Bonke, C. J. Larsen, N. Yavari, P. E. Nielsen, and H. Franzyk, “Antibacterial peptide nucleic acid–antimicrobial peptide (PNA–AMP) conjugates: antisense targeting of fatty acid biosynthesis,” Bioconjugate Chemistry, vol. 27, no. 4, pp. 863–867, 2016. View at: Publisher Site | Google Scholar
  149. S. H. E. Kaufmann, “Remembering Emil von Behring: from tetanus treatment to antibody cooperation with phagocytes,” MBio, vol. 8, no. 1, article e00117, 2017. View at: Publisher Site | Google Scholar
  150. S. H. E. Kaufmann, “Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff,” Nature Immunology, vol. 9, no. 7, pp. 705–712, 2008. View at: Publisher Site | Google Scholar
  151. A. Fleming, “On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae,” British Journal of Experimental Pathology, vol. 10, no. 3, p. 223, 1929. View at: Google Scholar
  152. A. M. Shukra, N. V. Sridevi, D. Chandran, and K. Maithal Ph.D, “Production of recombinant antibodies using bacteriophages,” European Journal of Microbiology and Immunology, vol. 4, no. 2, pp. 91–98, 2014. View at: Publisher Site | Google Scholar
  153. L. R. Berghman, D. Abi-Ghanem, S. D. Waghela, and S. C. Ricke, “Antibodies: an alternative for antibiotics?” Poultry Science, vol. 84, no. 4, pp. 660–666, 2005. View at: Publisher Site | Google Scholar
  154. L. Czaplewski, R. Bax, M. Clokie et al., “Alternatives to antibiotics—a pipeline portfolio review,” The Lancet Infectious Diseases, vol. 16, no. 2, pp. 239–251, 2016. View at: Publisher Site | Google Scholar
  155. S. M. Lehar, T. Pillow, M. Xu et al., “Novel antibody–antibiotic conjugate eliminates intracellular S. aureus,” Nature, vol. 527, no. 7578, pp. 323–328, 2015. View at: Publisher Site | Google Scholar
  156. M. J. McConnell, “Where are we with monoclonal antibodies for multidrug-resistant infections?” Drug Discovery Today, vol. 24, no. 5, pp. 1132–1138, 2019. View at: Publisher Site | Google Scholar
  157. J. C. Brown and M. E. Koshland, “Activation of antibody Fc function by antigen-induced conformational changes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 72, no. 12, pp. 5111–5115, 1975. View at: Publisher Site | Google Scholar
  158. S. K. Kochi, R. C. Johnson, and A. P. Dalmasso, “Complement-mediated killing of the Lyme disease spirochete Borrelia burgdorferi. Role of antibody in formation of an effective membrane attack complex,” The Journal of Immunology, vol. 146, no. 11, pp. 3964–3970, 1991. View at: Google Scholar
  159. M. Drogari-Apiranthitou, E. J. Kuijper, N. Dekker, and J. Dankert, “Complement activation and formation of the membrane attack complex on serogroup B Neisseria meningitidis in the presence or absence of serum bactericidal activity,” Infection and Immunity, vol. 70, no. 7, pp. 3752–3758, 2002. View at: Publisher Site | Google Scholar
  160. M. M. Frank, K. Joiner, and C. Hammer, “The function of antibody and complement in the lysis of bacteria,” Reviews of Infectious Diseases, vol. 9, Supplement_5, pp. S537–S545, 1987. View at: Publisher Site | Google Scholar
  161. E. Diago-Navarro, M. P. Motley, G. Ruiz-Peréz et al., “Novel, broadly reactive anticapsular antibodies against carbapenem-resistant Klebsiella pneumoniae protect from infection,” MBio, vol. 9, no. 2, 2018. View at: Publisher Site | Google Scholar
  162. S. Gulati, F. J. Beurskens, B. J. de Kreuk et al., “Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody,” PLoS Biology, vol. 17, no. 6, article e3000323, 2019. View at: Publisher Site | Google Scholar
  163. M. S. Edwards, A. Nicholson-Weller, C. J. Baker, and D. L. Kasper, “The role of specific antibody in alternative complement pathway-mediated opsonophagocytosis of type III, group B Streptococcus,” Journal of Experimental Medicine, vol. 151, no. 5, pp. 1275–1287, 1980. View at: Publisher Site | Google Scholar
  164. P. Ames, D. DesJardins, and G. B. Pier, “Opsonophagocytic killing activity of rabbit antibody to Pseudomonas aeruginosa mucoid exopolysaccharide,” Infection and Immunity, vol. 49, no. 2, pp. 281–285, 1985. View at: Publisher Site | Google Scholar
  165. R. Friedrich, P. Panizzi, P. Fuentes-Prior et al., “Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation,” Nature, vol. 425, no. 6957, pp. 535–539, 2003. View at: Publisher Site | Google Scholar
  166. M. McAdow, D. M. Missiakas, and O. Schneewind, “Staphylococcus aureus secretes coagulase and von Willebrand factor binding protein to modify the coagulation cascade and establish host infections,” Journal of Innate Immunity, vol. 4, no. 2, pp. 141–148, 2012. View at: Publisher Site | Google Scholar
  167. L. Thomer, O. Schneewind, and D. Missiakas, “Pathogenesis of Staphylococcus aureus bloodstream infections,” Annual Review of Pathology: Mechanisms of Disease, vol. 11, no. 1, pp. 343–364, 2016. View at: Publisher Site | Google Scholar
  168. L. Thomer, C. Emolo, V. Thammavongsa et al., “Antibodies against a secreted product of Staphylococcus aureus trigger phagocytic killing,” Journal of Experimental Medicine, vol. 213, no. 3, pp. 293–301, 2016. View at: Publisher Site | Google Scholar
  169. T. B. Nielsen, P. Pantapalangkoor, B. M. Luna et al., “Monoclonal antibody protects against Acinetobacter baumannii infection by enhancing bacterial clearance and evading sepsis,” The Journal of Infectious Diseases, vol. 216, no. 4, pp. 489–501, 2017. View at: Publisher Site | Google Scholar
  170. F. Brossier, M. Lévy, A. Landier, P. Lafaye, and M.̀. Mock, “Functional analysis of Bacillus anthracis protective antigen by using neutralizing monoclonal antibodies,” Infection and Immunity, vol. 72, no. 11, pp. 6313–6317, 2004. View at: Publisher Site | Google Scholar
  171. I. Harari, A. Donohue-Rolfe, G. Keusch, and R. Arnon, “Synthetic peptides of Shiga toxin B subunit induce antibodies which neutralize its biological activity,” Infection and Immunity, vol. 56, no. 6, pp. 1618–1624, 1988. View at: Publisher Site | Google Scholar
  172. S. F. Little, S. H. Leppla, and E. Cora, “Production and characterization of monoclonal antibodies to the protective antigen component of Bacillus anthracis toxin,” Infection and Immunity, vol. 56, no. 7, pp. 1807–1813, 1988. View at: Publisher Site | Google Scholar
  173. R. J. Collier and J. A. T. Young, “Anthrax toxin,” Annual Review of Cell and Developmental Biology, vol. 19, no. 1, pp. 45–70, 2003. View at: Publisher Site | Google Scholar
  174. T.-S. Migone, G. M. Subramanian, J. Zhong et al., “Raxibacumab for the treatment of inhalational anthrax,” New England Journal of Medicine, vol. 361, no. 2, pp. 135–144, 2009. View at: Publisher Site | Google Scholar
  175. S. L. Greig, “Obiltoxaximab: first global approval,” Drugs, vol. 76, no. 7, pp. 823–830, 2016. View at: Publisher Site | Google Scholar
  176. J. H. Melehani, D. B. A. James, A. L. DuMont, V. J. Torres, and J. A. Duncan, “Staphylococcus aureus leukocidin A/B (LukAB) kills human monocytes via host NLRP3 and ASC when extracellular, but not intracellular,” PLoS Pathogens, vol. 11, no. 6, article e1004970, 2015. View at: Publisher Site | Google Scholar
  177. I. P. Thomsen, G. Sapparapu, D. B. A. James et al., “Monoclonal antibodies against the Staphylococcus aureus bicomponent leukotoxin AB isolated following invasive human infection reveal diverse binding and modes of action,” The Journal of Infectious Diseases, vol. 215, no. 7, pp. 1124–1131, 2017. View at: Publisher Site | Google Scholar
  178. C. Tkaczyk, M. M. Hamilton, A. Sadowska et al., “Targeting alpha toxin and ClfA with a multimechanistic monoclonal-antibody-based approach for prophylaxis of SeriousStaphylococcus aureusDisease,” MBio, vol. 7, no. 3, article e00528, 2016. View at: Publisher Site | Google Scholar
  179. C. Tkaczyk, L. Hua, R. Varkey et al., “Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency,” Clinical and Vaccine Immunology, vol. 19, no. 3, pp. 377–385, 2012. View at: Publisher Site | Google Scholar
  180. X.-Q. Yu, G. J. Robbie, Y. Wu et al., “Safety, tolerability, and pharmacokinetics of MEDI 4893, an investigational, extended-half-life, anti-Staphylococcus aureus alpha-toxin human monoclonal antibody, in healthy adults,” Antimicrobial Agents and Chemotherapy, vol. 61, no. 1, article e01020, 2017. View at: Publisher Site | Google Scholar
  181. H. Rouha, A. Badarau, Z. C. Visram et al., “Five birds, one stone: neutralization of α-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibody,” in MAbs, pp. 243–254, Taylor & Francis, 2015. View at: Google Scholar
  182. Z. Magyarics, F. Leslie, J. Bartko et al., “Randomized, double-blind, placebo-controlled, single-ascending-dose study of the penetration of a monoclonal antibody combination (ASN100) TargetingStaphylococcus aureusCytotoxins in the lung epithelial lining fluid of healthy volunteers,” Antimicrobial Agents and Chemotherapy, vol. 63, no. 8, article e00350, 2019. View at: Publisher Site | Google Scholar
  183. B. François, E. Mercier, C. Gonzalez et al., “Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused by Staphylococcus aureus: first-in-human trial,” Intensive Care Medicine, vol. 44, no. 11, pp. 1787–1796, 2018. View at: Publisher Site | Google Scholar
  184. A. K. Varshney, G. A. Kuzmicheva, J. Lin et al., “A natural human monoclonal antibody targeting Staphylococcus protein A protects against Staphylococcus aureus bacteremia,” PLoS One, vol. 13, no. 1, article e0190537, 2018. View at: Publisher Site | Google Scholar
  185. T. Huynh, M. Stecher, J. Mckinnon, N. Jung, and M. E. Rupp, “Safety and tolerability of 514G3, a true human anti-protein a monoclonal antibody for the treatment of S. aureus bacteremia,” in Open Forum Infectious Diseases, vol. 3, Supplement_1, Oxford University Press, 2016. View at: Publisher Site | Google Scholar
  186. T. Secher, L. Fauconnier, A. Szade et al., “Anti-Pseudomonas aeruginosa serotype O11 LPS immunoglobulin M monoclonal antibody panobacumab (KBPA101) confers protection in a murine model of acute lung infection,” Journal of Antimicrobial Chemotherapy, vol. 66, no. 5, pp. 1100–1109, 2011. View at: Publisher Site | Google Scholar
  187. J. T. Thaden, A. E. Keller, N. J. Shire et al., “Pseudomonas aeruginosaBacteremic patients exhibit nonprotective antibody titers against therapeutic antibody targets PcrV and Psl exopolysaccharide,” The Journal of Infectious Diseases, vol. 213, no. 4, pp. 640–648, 2016. View at: Publisher Site | Google Scholar
  188. S. O. Ali, X. Q. Yu, G. J. Robbie et al., “Phase 1 study of MEDI3902, an investigational anti–Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults,” Clinical Microbiology and Infection, vol. 25, no. 5, pp. 629.e1–629.e6, 2019. View at: Publisher Site | Google Scholar
  189. A. DiGiandomenico, A. E. Keller, C. Gao et al., “A multifunctional bispecific antibody protects against Pseudomonas aeruginosa,” Science Translational Medicine, vol. 6, no. 262, article 262ra155, 2014. View at: Publisher Site | Google Scholar
  190. P. Warrener, R. Varkey, J. C. Bonnell et al., “A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 8, pp. 4384–4391, 2014. View at: Publisher Site | Google Scholar
  191. R. Jain, V. V. Beckett, M. W. Konstan et al., “KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa,” Journal of Cystic Fibrosis, vol. 17, no. 4, pp. 484–491, 2018. View at: Publisher Site | Google Scholar
  192. C.-W. Tsai and S. Morris, “Approval of raxibacumab for the treatment of inhalation anthrax under the US Food and Drug Administration “Animal Rule”,” Frontiers in Microbiology, vol. 6, article 1320, 2015. View at: Publisher Site | Google Scholar
  193. B. Biron, K. Beck, D. Dyer, M. Mattix, N. Twenhafel, and A. Nalca, “Efficacy of ETI-204 monoclonal antibody as an adjunct therapy in a New Zealand white rabbit partial survival model for inhalational anthrax,” Antimicrobial Agents and Chemotherapy, vol. 59, no. 4, pp. 2206–2214, 2015. View at: Publisher Site | Google Scholar
  194. C. D. Alonso and M. V. Mahoney, “Bezlotoxumab for the prevention of Clostridium difficile infection: a review of current evidence and safety profile,” Infection and Drug Resistance, vol. 12, pp. 1–9, 2019. View at: Publisher Site | Google Scholar
  195. G. J. Babcock, T. J. Broering, H. J. Hernandez et al., “Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters,” Infection and Immunity, vol. 74, no. 11, pp. 6339–6347, 2006. View at: Publisher Site | Google Scholar
  196. M. Bitzan, R. Poole, M. Mehran et al., “Safety and pharmacokinetics of chimeric anti-Shiga toxin 1 and anti-Shiga toxin 2 monoclonal antibodies in healthy volunteers,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 7, pp. 3081–3087, 2009. View at: Publisher Site | Google Scholar
  197. S. C. Alley, N. M. Okeley, and P. D. Senter, “Antibody–drug conjugates: targeted drug delivery for cancer,” Current Opinion in Chemical Biology, vol. 14, no. 4, pp. 529–537, 2010. View at: Publisher Site | Google Scholar
  198. E. L. Sievers and P. D. Senter, “Antibody-drug conjugates in cancer therapy,” Annual Review of Medicine, vol. 64, no. 1, pp. 15–29, 2013. View at: Publisher Site | Google Scholar
  199. M. Abdollahpour-Alitappeh, M. Lotfinia, T. Gharibi et al., “Antibody-drug conjugates (ADCs) for cancer therapy: strategies, challenges, and successes,” Journal of Cellular Physiology, vol. 234, no. 5, pp. 5628–5642, 2019. View at: Publisher Site | Google Scholar
  200. A. Thomas, B. A. Teicher, and R. Hassan, “Antibody–drug conjugates for cancer therapy,” The Lancet Oncology, vol. 17, no. 6, pp. e254–e262, 2016. View at: Publisher Site | Google Scholar
  201. S. Ranghar, P. Sirohi, P. Verma, and V. Agarwal, “Nanoparticle-based drug delivery systems: promising approaches against infections,” Brazilian Archives of Biology and Technology, vol. 57, no. 2, pp. 209–222, 2014. View at: Publisher Site | Google Scholar
  202. D. Pissuwan, C. H. Cortie, S. M. Valenzuela, and M. B. Cortie, “Functionalised gold nanoparticles for controlling pathogenic bacteria,” Trends in Biotechnology, vol. 28, no. 4, pp. 207–213, 2010. View at: Publisher Site | Google Scholar
  203. W. Gao, Y. Chen, Y. Zhang, Q. Zhang, and L. Zhang, “Nanoparticle-based local antimicrobial drug delivery,” Advanced Drug Delivery Reviews, vol. 127, pp. 46–57, 2018. View at: Publisher Site | Google Scholar
  204. W. Gao, S. Thamphiwatana, P. Angsantikul, and L. Zhang, “Nanoparticle approaches against bacterial infections,” Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology, vol. 6, no. 6, pp. 532–547, 2014. View at: Publisher Site | Google Scholar
  205. R. Y. Pelgrift and A. J. Friedman, “Nanotechnology as a therapeutic tool to combat microbial resistance,” Advanced Drug Delivery Reviews, vol. 65, no. 13-14, pp. 1803–1815, 2013. View at: Publisher Site | Google Scholar
  206. A. Gupta, S. Mumtaz, C.-H. Li, I. Hussain, and V. M. Rotello, “Combatting antibiotic-resistant bacteria using nanomaterials,” Chemical Society Reviews, vol. 48, no. 2, pp. 415–427, 2019. View at: Publisher Site | Google Scholar
  207. C. Buzea, I. I. Pacheco, and K. Robbie, “Nanomaterials and nanoparticles: sources and toxicity,” Biointerphases, vol. 2, no. 4, pp. MR17–MR71, 2007. View at: Publisher Site | Google Scholar
  208. F. ud Din, W. Aman, I. Ullah et al., “Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors,” International Journal of Nanomedicine, vol. 12, pp. 7291–7309, 2017. View at: Publisher Site | Google Scholar
  209. S. Shen, Y. Wu, Y. Liu, and D. Wu, “High drug-loading nanomedicines: progress, current status, and prospects,” International Journal of Nanomedicine, vol. 12, pp. 4085–4109, 2017. View at: Publisher Site | Google Scholar
  210. T. Akagi, M. Baba, and M. Akashi, “Preparation of nanoparticles by the self-organization of polymers consisting of hydrophobic and hydrophilic segments: potential applications,” Polymer, vol. 48, no. 23, pp. 6729–6747, 2007. View at: Publisher Site | Google Scholar
  211. G. Franci, A. Falanga, S. Galdiero et al., “Silver nanoparticles as potential antibacterial agents,” Molecules, vol. 20, no. 5, pp. 8856–8874, 2015. View at: Publisher Site | Google Scholar
  212. R. E. Morsi, A. M. Alsabagh, S. A. Nasr, and M. M. Zaki, “Multifunctional nanocomposites of chitosan, silver nanoparticles, copper nanoparticles and carbon nanotubes for water treatment: antimicrobial characteristics,” International Journal of Biological Macromolecules, vol. 97, pp. 264–269, 2017. View at: Publisher Site | Google Scholar
  213. A. Mukhopadhyay, S. Basu, S. Singha, and H. K. Patra, “Inner-view of nanomaterial incited protein conformational changes: insights into designable interaction,” Research, vol. 2018, article 9712832, 15 pages, 2018. View at: Publisher Site | Google Scholar
  214. J. Tang, Q. Chen, L. Xu et al., “Graphene oxide–silver nanocomposite as a highly effective antibacterial agent with species-specific mechanisms,” ACS Applied Materials & Interfaces, vol. 5, no. 9, pp. 3867–3874, 2013. View at: Publisher Site | Google Scholar
  215. X. Yang, Q. Wei, H. Shao, and X. Jiang, “Multivalent aminosaccharide-based gold nanoparticles as narrow-spectrum antibiotics in vivo,” ACS Applied Materials & Interfaces, vol. 11, no. 8, pp. 7725–7730, 2019. View at: Publisher Site | Google Scholar
  216. L. Salvioni, E. Galbiati, V. Collico et al., “Negatively charged silver nanoparticles with potent antibacterial activity and reduced toxicity for pharmaceutical preparations,” International Journal of Nanomedicine, vol. 12, pp. 2517–2530, 2017. View at: Publisher Site | Google Scholar
  217. B. Lu, F. Lu, L. Ran et al., “Imidazole-molecule-capped chitosan–gold nanocomposites with enhanced antimicrobial activity for treating biofilm-related infections,” Journal of Colloid and Interface Science, vol. 531, pp. 269–281, 2018. View at: Publisher Site | Google Scholar
  218. W. Xiu, S. Gan, Q. Wen et al., “Biofilm microenvironment-responsive nanotheranostics for dual-mode imaging and hypoxia-relief-enhanced photodynamic therapy of bacterial infections,” Research, vol. 2020, article 9426453, 15 pages, 2020. View at: Publisher Site | Google Scholar
  219. W. Chen, S. Li, P. Renick et al., “Bacterial acidity-triggered antimicrobial activity of self-assembling peptide nanofibers,” Journal of Materials Chemistry B, vol. 7, no. 18, pp. 2915–2919, 2019. View at: Publisher Site | Google Scholar
  220. A. F. Radovic-Moreno, T. K. Lu, V. A. Puscasu, C. J. Yoon, R. Langer, and O. C. Farokhzad, “Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics,” ACS Nano, vol. 6, no. 5, pp. 4279–4287, 2012. View at: Publisher Site | Google Scholar
  221. M. H. Xiong, Y. J. Li, Y. Bao, X. Z. Yang, B. Hu, and J. Wang, “Bacteria-responsive multifunctional nanogel for targeted antibiotic delivery,” Advanced Materials, vol. 24, no. 46, pp. 6175–6180, 2012. View at: Publisher Site | Google Scholar
  222. A. Regnier-Vigouroux, “The mannose receptor in the brain,” International Review of Cytology, vol. 226, pp. 321–342, 2003. View at: Publisher Site | Google Scholar
  223. S. Ghanbar, M. Fumakia, E. A. Ho, and S. Liu, “A new strategy for battling bacterial resistance: turning potent, non-selective and potentially non-resistance-inducing biocides into selective ones,” Nanomedicine, vol. 14, no. 2, pp. 471–481, 2018. View at: Publisher Site | Google Scholar
  224. S. Hussain, J. Joo, J. Kang et al., “Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy,” Nature Biomedical Engineering, vol. 2, no. 2, pp. 95–103, 2018. View at: Publisher Site | Google Scholar
  225. C. Y. Zhang, J. Gao, and Z. Wang, “Bioresponsive nanoparticles targeted to infectious microenvironments for sepsis management,” Advanced Materials, vol. 30, no. 43, article e1803618, 2018. View at: Publisher Site | Google Scholar
  226. P. Horvath and R. Barrangou, “CRISPR/Cas, the immune system of bacteria and archaea,” Science, vol. 327, no. 5962, pp. 167–170, 2010. View at: Publisher Site | Google Scholar
  227. E. V. Koonin, K. S. Makarova, and F. Zhang, “Diversity, classification and evolution of CRISPR-Cas systems,” Current Opinion in Microbiology, vol. 37, pp. 67–78, 2017. View at: Publisher Site | Google Scholar
  228. K. S. Makarova, Y. I. Wolf, O. S. Alkhnbashi et al., “An updated evolutionary classification of CRISPR–Cas systems,” Nature Reviews Microbiology, vol. 13, no. 11, pp. 722–736, 2015. View at: Publisher Site | Google Scholar
  229. M.-N. Hsu, Y.-H. Chang, V. A. Truong, P.-L. Lai, T. K. N. Nguyen, and Y.-C. Hu, “CRISPR technologies for stem cell engineering and regenerative medicine,” Biotechnology Advances, vol. 37, no. 8, p. 107447, 2019. View at: Publisher Site | Google Scholar
  230. A. Pickar-Oliver and C. A. Gersbach, “The next generation of CRISPR–Cas technologies and applications,” Nature Reviews Molecular Cell Biology, vol. 20, no. 8, pp. 490–507, 2019. View at: Publisher Site | Google Scholar
  231. R. J. Citorik, M. Mimee, and T. K. Lu, “Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases,” Nature Biotechnology, vol. 32, no. 11, pp. 1141–1145, 2014. View at: Publisher Site | Google Scholar
  232. D. Bikard, C. W. Euler, W. Jiang et al., “Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials,” Nature Biotechnology, vol. 32, no. 11, pp. 1146–1150, 2014. View at: Publisher Site | Google Scholar
  233. E. Pursey, D. Sunderhauf, W. H. Gaze, E. R. Westra, and S. van Houte, “CRISPR-Cas antimicrobials: challenges and future prospects,” PLoS Pathogens, vol. 14, no. 6, article e1006990, 2018. View at: Publisher Site | Google Scholar
  234. G. Ram, H. F. Ross, R. P. Novick, I. Rodriguez-Pagan, and D. Jiang, “Conversion of staphylococcal pathogenicity islands to CRISPR-carrying antibacterial agents that cure infections in mice,” Nature Biotechnology, vol. 36, no. 10, pp. 971–976, 2018. View at: Publisher Site | Google Scholar
  235. A. E. Dolan, Z. Hou, Y. Xiao et al., “Introducing a spectrum of long-range genomic deletions in human embryonic stem cells using type I CRISPR-Cas,” Molecular Cell, vol. 74, no. 5, pp. 936–950.e5, 2019. View at: Publisher Site | Google Scholar
  236. C. Hidalgo-Cantabrana, Y. J. Goh, M. Pan, R. Sanozky-Dawes, and R. Barrangou, “Genome editing using the endogenous type I CRISPR-Cas system inLactobacillus crispatus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 32, pp. 15774–15783, 2019. View at: Publisher Site | Google Scholar
  237. N. Gilbert, “Four stories of antibacterial breakthroughs,” Nature, vol. 555, no. 7695, pp. S5–S7, 2018. View at: Publisher Site | Google Scholar
  238. K. V. Brown, “Scientists are creating a genetic chainsaw to hack superbug DNA to bits,” 2017, View at: Google Scholar
  239. B. K. Warner, J. K. Alder, and A. Suli, “Genome editing in zebrafish using CRISPR-Cas9: applications for developmental toxicology,” in Developmental Toxicology: Methods and Protocols, vol. 1965, pp. 235–250, Springer, 2019. View at: Publisher Site | Google Scholar
  240. F. J. Sánchez-Rivera and T. Jacks, “Applications of the CRISPR–Cas9 system in cancer biology,” Nature Reviews Cancer, vol. 15, no. 7, pp. 387–393, 2015. View at: Publisher Site | Google Scholar
  241. C. Liu, L. Zhang, H. Liu, and K. Cheng, “Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications,” Journal of Controlled Release, vol. 266, pp. 17–26, 2017. View at: Publisher Site | Google Scholar
  242. R. Sundaresan, H. P. Parameshwaran, S. D. Yogesha, M. W. Keilbarth, and R. Rajan, “RNA-independent DNA cleavage activities of Cas9 and Cas12a,” Cell Reports, vol. 21, no. 13, pp. 3728–3739, 2017. View at: Publisher Site | Google Scholar
  243. J. S. Chen, E. Ma, L. B. Harrington et al., “CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity,” Science, vol. 360, no. 6387, pp. 436–439, 2018. View at: Publisher Site | Google Scholar
  244. M. A. English, L. R. Soenksen, R. V. Gayet et al., “Programmable CRISPR-responsive smart materials,” Science, vol. 365, no. 6455, pp. 780–785, 2019. View at: Publisher Site | Google Scholar
  245. I. Sekirov, S. L. Russell, L. C. M. Antunes, and B. B. Finlay, “Gut microbiota in health and disease,” Physiological Reviews, vol. 90, no. 3, pp. 859–904, 2010. View at: Publisher Site | Google Scholar
  246. I. Y. Hwang, H. L. Lee, J. G. Huang et al., “Engineering microbes for targeted strikes against human pathogens,” Cellular and Molecular Life Sciences, vol. 75, no. 15, pp. 2719–2733, 2018. View at: Publisher Site | Google Scholar
  247. E. Bakkeren, J. S. Huisman, S. A. Fattinger et al., “Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut,” Nature, vol. 573, no. 7773, pp. 276–280, 2019. View at: Publisher Site | Google Scholar
  248. J. Bilinski, P. Grzesiowski, N. Sorensen et al., “Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study,” Clinical Infectious Diseases, vol. 65, no. 3, pp. 364–370, 2017. View at: Publisher Site | Google Scholar
  249. A. R. Manges, T. S. Steiner, and A. J. Wright, “Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review,” Infectious Diseases, vol. 48, no. 8, pp. 587–592, 2016. View at: Publisher Site | Google Scholar
  250. J. Biliński, P. Grzesiowski, J. Muszyński et al., “Fecal microbiota transplantation inhibits multidrug-resistant gut pathogens: preliminary report performed in an immunocompromised host,” Archivum Immunologiae et Therapiae Experimentalis, vol. 64, no. 3, pp. 255–258, 2016. View at: Publisher Site | Google Scholar
  251. Y. Taur and E. G. Pamer, “Harnessing microbiota to kill a pathogen: fixing the microbiota to treat Clostridium difficile infections,” Nature Medicine, vol. 20, no. 3, pp. 246-247, 2014. View at: Publisher Site | Google Scholar
  252. J. S. Bakken, T. Borody, L. J. Brandt et al., “Treating Clostridium difficile infection with fecal microbiota transplantation,” Clinical Gastroenterology and Hepatology, vol. 9, no. 12, pp. 1044–1049, 2011. View at: Publisher Site | Google Scholar
  253. T. J. Borody, L. J. Brandt, S. Paramsothy, and G. Agrawal, “Fecal microbiota transplantation: a new standard treatment option for Clostridium difficile infection,” Expert Review of Anti-Infective Therapy, vol. 11, no. 5, pp. 447–449, 2014. View at: Publisher Site | Google Scholar
  254. E. G. Pamer, “Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens,” Science, vol. 352, no. 6285, pp. 535–538, 2016. View at: Publisher Site | Google Scholar
  255. M. Kaleko, J. A. Bristol, S. Hubert et al., “Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection,” Anaerobe, vol. 41, pp. 58–67, 2016. View at: Publisher Site | Google Scholar
  256. Y. T. Li, H. F. Cai, Z. H. Wang, J. Xu, and J. Y. Fang, “Systematic review with meta-analysis: long-term outcomes of faecal microbiota transplantation for Clostridium difficile infection,” Alimentary Pharmacology & Therapeutics, vol. 43, no. 4, pp. 445–457, 2016. View at: Publisher Site | Google Scholar
  257. W. M. Tauxe, T. Dhere, A. Ward, L. D. Racsa, J. B. Varkey, and C. S. Kraft, “Fecal microbiota transplant protocol for Clostridium difficile infection,” Laboratory Medicine, vol. 46, no. 1, pp. e19–e23, 2015. View at: Publisher Site | Google Scholar
  258. Z. Kassam, C. H. Lee, Y. Yuan, and R. H. Hunt, “Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis,” The American Journal of Gastroenterology, vol. 108, no. 4, pp. 500–508, 2013. View at: Publisher Site | Google Scholar
  259. U S Food & Drug Administration, “Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms,” September 2019, View at: Google Scholar
  260. M. Bermudez-Brito, J. Plaza-Díaz, S. Muñoz-Quezada, C. Gómez-Llorente, and A. Gil, “Probiotic mechanisms of action,” Annals of Nutrition and Metabolism, vol. 61, no. 2, pp. 160–174, 2012. View at: Publisher Site | Google Scholar
  261. V. C. Harris, B. W. Haak, M. Boele van Hensbroek, and W. J. Wiersinga, “The intestinal microbiome in infectious diseases: the clinical relevance of a rapidly emerging field,” in Open forum infectious diseases, vol. 4, no. 3, Oxford University Press, 2017. View at: Publisher Site | Google Scholar
  262. C. Lau and R. Chamberlain, “Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis,” International Journal of General Medicine, vol. 9, pp. 27–37, 2016. View at: Publisher Site | Google Scholar
  263. N. Saeidi, C. K. Wong, T. M. Lo et al., “Engineering microbes to sense and eradicatePseudomonas aeruginosa, a human pathogen,” Molecular Systems Biology, vol. 7, no. 1, p. 521, 2011. View at: Publisher Site | Google Scholar
  264. I. Y. Hwang, E. Koh, A. Wong et al., “Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models,” Nature Communications, vol. 8, no. 1, article 15028, 2017. View at: Publisher Site | Google Scholar
  265. R. Lopez-Igual, J. Bernal-Bayard, A. Rodriguez-Paton, J. M. Ghigo, and D. Mazel, “Engineered toxin-intein antimicrobials can selectively target and kill antibiotic-resistant bacteria in mixed populations,” Nature Biotechnology, vol. 37, no. 7, pp. 755–760, 2019. View at: Publisher Site | Google Scholar

Copyright © 2020 Zifang Shang et al. Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0).

 PDF Download Citation Citation
Altmetric Score