New Class Of Antibiotics Research Articles

Micromolar Concentrations of Methionine Aminopeptidase Inhibitor has Little Cytotoxic Effect on Cancerous and Non‐Cancerous Mammalian Cells

Tuberculosis (TB) is a disease of the lung caused by the bacterium, Mycobacterium tuberculosis (Mtb), and is the second leading cause of mortality from an infectious agent after SARS‐CoV‐2. Mtb is an opportunistic pathogen that benefits from a compromised immune system and is particularly deadly in HIV patients. New therapies targeting TB are necessary due to an increase in multi‐drug resistant strains. Our collaborators at Texas Southern University identified novel bacterial methionine aminopeptidase (MtMetAP1) inhibitors. Genetic knockout studies support the lethality of the deletion of MtMetAP1 in Mtb. Further studies support the existence of an ortholog in Homo sapiens (HsMetAP1) that performs similar essential functions. Although these novel inhibitors are known to be effective against Mtb, their cytotoxicity in mammalian cells has yet to be established. We hypothesize that there will be low levels of cytotoxicity in cancerous and primary lung cell lines at varying concentrations of the MetAP novel inhibitor, UST‐001. Using flow cytometry via a MUSE® Cell Count and Viability Kit, the cytotoxicity of UST‐001 was assayed in H1299 cancer cells. The H1299 cells were exposed to concentrations of UST‐001 ranging from 0.1μM to 750μM for 48 hours at 37℃and 5% CO2. Three negative controls were included in each replicate: DMSO (carrier), pure media, and Isoniazid (INH). INH is a common clinically effective TB treatment. The viability of H1299 cells was still over 60% at the highest inhibitor concentration tested. Trypan Blue Assays were performed on the same H1299 cells at each concentration and the controls, which corroborated flow cytometry results. In establishment of a dose‐response curve, our data showed that at UST‐001 concentrations below 100 μM, induced little to no cell death and cell viability of 90% or higher. Since cancerous cells have higher mitotic rates and more repair pathways, we hypothesize that we will be able to establish an IC50 curve in non‐cancerous Mlg‐2908 lung fibroblast cells at higher concentrations. Current flow cytometry testing on Mlg‐2908 cells, using the same protocol as the H1299 cells, shows cell viability of 89% or higher in 0.1 μM to 10 μM UST‐001 concentrations. Since cancerous cells have higher mitotic rates and more repair pathways, we hypothesize that we will be able to establish an IC50 curve in Mlg‐2908 cells at higher concentrations. Further studies using a Muse Annexin V apoptosis assay will focus on the UST‐001 mechanism of cell death. Our ultimate goal is to characterize the toxicity of this drug in mammalian systems, with hopes of potentially identifying a new class of antibiotics and pharmaceutical targets.

The Next Pandemic

The Next Pandemic

Recent Advances in Green Synthesis, Characterization, and Applications of Bioactive Metallic Nanoparticles.

Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in applied research. Biogenic synthesis of NPs is more desirable than physical and chemical synthesis due to its eco-friendliness, non-toxicity, lower energy consumption, and multifunctional nature. Plants outperform microorganisms as reducing agents as they contain large secondary biomolecules that accelerate the reduction and stability of the NPs. The produced NPs can then be studied spectroscopically (UV-Visible, XRD, Raman, IR, etc.) and microscopically (SEM, TEM, AFM, etc.). The biological reduction of a metallic ion or its oxide to a nanoparticle is quick, simple, and may be scaled up at room temperature and pressure. The rise in multi-drug resistant (MDR) microbes due to the immoderate use of antibiotics in non-infected patients is a major cause of morbidity and mortality in humans. The contemporary development of a new class of antibiotics with different mechanisms of action to kill microbes is crucial. Metals and their oxides are extremely toxic to microbes at unprecedentedly low concentrations. In addition, prevailing infections in plants and animals are raising significant concerns across the globe. NPs’ wide range of bioactivity makes them ideal antimicrobial agents in agricultural and medical fields. The present review outlines the synthesis of metallic NPs from botanicals, which enables the metals to be in a stabilized form even after ionization. It also presents a valuable database on the biofunctionalization of synthesized NPs for further drug development.

Nocathiacin, Thiazomycin, and Polar Analogs Are Highly Effective Agents against Toxigenic Clostridioides difficile.

Clostridioides difficile is a commensal Gram-positive gut bacterium that causes C. difficile-associated diarrhea. Currently available antibacterial therapeutic treatment options are effective except for the repeated recurrences significantly burdening the health care system and causing mortality. The development of new therapeutic modalities including new effective antibiotics with a low rate of recurrence has been unpredictive and exceedingly challenging, requiring continued profiling of many new classes of antibiotics. Nocathiacins and thiazomycins are a class of thiazolyl peptides exhibiting potent and selective broad-spectrum Gram-positive activity including activity against the anaerobe C. difficile. These compounds showed MIC values of 0.015-0.06 μg/mL against C. difficile with more than 100-200-fold selectivity versus commensurate Gram-negative Bacteroides fragilis. Nocathiacin I and one of its analogs exhibited potent in vivo efficacy in the gold-standard hamster model of C. difficile infection, providing 100% protection in this lethal model at 6.25 mg/kg orally twice daily. The efficacy was corroborated by robust reduction of cecum C. difficile burden and proportionate exposure of the compounds in the cecum contents without any systemic absorption. In this paper, details of the results of in vitro, in vivo, pharmacodynamics, and pharmacokinetic studies have been described.

Pleuromutilin and its Derivatives: Promising Novel Anti-Infective Agents

: Due to the emergence and spread of the drug resistance to numerous antibiotics, global research attempts focus on new classes of antibiotics with different mechanisms of action from currently used drugs. Pleuromutilin was first identified as a natural antibiotic in 1951 from the New York Botanical Garden and Columbia University. The substance was isolated from Pleurotus mutilus and Pleurotus passeckerianus. Nevertheless, pleuromutilin was first launched in 1979 (tiamulin) for use in veterinarians. However, antibiotics with new targets or employing a different action mechanism are always attractive because they conquered recognized resistance by the bacteria and were not resisted against approved antibiotic classes. Pleuromutilin has a unique antibacterial activity that binds to the peptidyl transferase at the central area of the bacteria's 50S ribosome to inhibit protein synthesis. Pleuromutilin antibiotics have antimicrobial activity against Gram-positive pathogens. Besides, they cover some fastidious Gram-negative bacteria. As Gram-positive bacteria increased resistance against currently approved antibiotics, the pleuromutilin antibiotic was investigated to develop a systemically antibacterial drug to be used in humans. In 2006, lefamulin was developed and started to encounter studying for systemic infection in humans. Lefamulin is a semisynthetic pleuromutilin antibiotic, and the US FDA approved it for community-acquired bacterial pneumonia (CABP) treatment in August 2019. This review will focus on this antibiotic's critical issues, the relevant bacterial spectrum activity, preclinical and clinical information, and potentially therapeutic properties of pleuromutilin antibiotic.

Catheter-Associated Urinary Tract Infections: Current Challenges and Future Prospects.

Catheter-associated urinary tract infection (CAUTI) is the most common healthcare-associated infection and cause of secondary bloodstream infections. Despite many advances in diagnosis, prevention and treatment, CAUTI remains a severe healthcare burden, and antibiotic resistance rates are alarmingly high. In this review, current CAUTI management paradigms and challenges are discussed, followed by future prospects as they relate to the diagnosis, prevention, and treatment. Clinical and translational evidence will be evaluated, as will key basic science studies that underlie preventive and therapeutic approaches. Novel diagnostic strategies and treatment decision aids under development will decrease the time to diagnosis and improve antibiotic accuracy and stewardship. These include several classes of biomarkers often coupled with artificial intelligence algorithms, cell-free DNA, and others. New preventive strategies including catheter coatings and materials, vaccination, and bacterial interference are being developed and investigated. The antibiotic pipeline remains insufficient, and new strategies for the identification of new classes of antibiotics, and rational design of small molecule inhibitor alternatives, are under development for CAUTI treatment.

Novel benzothiazole‒urea hybrids: Design, synthesis and biological activity as potent anti-bacterial agents against MRSA

Novel benzothiazole‒urea hybrids were designed, synthesized and evaluated their anti-bacterial activity. They only exhibited anti-bacterial activity against Gram-positive bacteria, including clinical methicillin-resistant S. aureus (MRSA), compounds 5f, 5i, 8e, 8k and 8l exhibited potent activity (MIC = 0.39 and 0.39/0.78 μM against SA and MRSA, respectively). Crystal violet assay showed that compounds 5f, 8e and 8l not only inhibited the formation of biofilms but also eradicated preformed biofilms. Compound 8l had membrane disruption, little propensity to induce resistance, benign safety and in vivo anti-MRSA efficacy in a mouse model of abdominal infection. Therefore, our data demonstrated the potential to advance benzothiazole‒urea hybrids as a new class of antibiotics.

The Bacterial Cell Wall: From Lipid II Flipping to Polymerization.

The peptidoglycan (PG) cell wall is an extra-cytoplasmic glycopeptide polymeric structure that protects bacteria from osmotic lysis and determines cellular shape. Since the cell wall surrounds the cytoplasmic membrane, bacteria must add new material to the PG matrix during cell elongation and division. The lipid-linked precursor for PG biogenesis, Lipid II, is synthesized in the inner leaflet of the cytoplasmic membrane and is subsequently translocated across the bilayer so that the PG building block can be polymerized and cross-linked by complex multiprotein machines. This review focuses on major discoveries that have significantly changed our understanding of PG biogenesis in the past decade. In particular, we highlight progress made toward understanding the translocation of Lipid II across the cytoplasmic membrane by the MurJ flippase, as well as the recent discovery of a novel class of PG polymerases, the SEDS (shape, elongation, division, and sporulation) glycosyltransferases RodA and FtsW. Since PG biogenesis is an effective target of antibiotics, these recent developments may lead to the discovery of much-needed new classes of antibiotics to fight bacterial resistance.

In Silico and In Vitro Screening of Natural Compounds as Broad-Spectrum β-Lactamase Inhibitors against Acinetobacter baumannii New Delhi Metallo-β-lactamase-1 (NDM-1).

Antibiotic resistance is one of the significant problems globally; there is an increase in resistance with introducing every new class of antibiotics. Further, this has become one of the reasons for arising of new resistance mechanisms in Acinetobacter baumannii. In this study, we have screened natural compounds as a possible inhibitor against the NDM-1 β-lactamase enzyme from A. baumannii using a combination of in silico methods and in vitro evaluation. The database of natural compounds was screened against NDM-1 protein, using Glide docking, followed by QM-polarised ligand docking (QPLD). When the screened hits were validated in vitro, withaferin A and mangiferin had good IC50 values in reducing the activity of NDM-1 enzymes, and their fractional inhibitory concentration index (FICI) was ascertained in combination with imipenem. The withaferin A and mangiferin-NDM-1 docking complexes were analyzed for structural stability by molecular dynamic simulation analysis using GROMACS for 100 ns. The molecular properties of the natural compounds were then calculated using density functional theory (DFT). Withaferin A and mangiferin showed promising inhibitory activity and can be a natural compound candidate inhibitor synergistically used along with carbapenems against NDM-1 producing A. baumannii.

Acridinium-conjugated aromatic heterocycles as highly potent FtsZ inhibitors: Design, synthesis, and biological evaluation.

The epidemic of multidrug resistance (MDR) is a serious threat to public health, and new classes of antibiotics with novel mechanisms of action are in critical need. We rationally designed and efficiently synthesized three series of new chemical entities with potential antibacterial activity targeting filamenting temperature-sensitive mutant Z (FtsZ). Evaluation of these compounds against a panel of Gram-positive bacteria including MDR and vancomycin-resistant Enterococcusstrains indicated that most compounds showed enhanced antibacterial efficacy, comparable or even superior to the reference drugs. The newly synthesized compounds proved to be substrates of the Escherichia coli efflux pump AcrB, thus affecting the activity. Their structure-activity relationshipswere summarized in detail. The most potent compound 10f quickly eliminated bacteria in a bactericidal mode, with low susceptibility to induce bacterial resistance. Further mechanistic studies with the BsFtsZ protein revealed that 10f functioned as an effective FtsZ inhibitor through altering the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which leads to inhibition of cell division and cell death. Besides, 10f not only displayed no obvious cytotoxicity to mammalian cells but also had a high efficacy in a murine model of bacteremia in vivo. Regarded as a whole, our findings highlight 10f as a promising new FtsZ-targeting bactericidal agent.

Bioinspired Polydopamine Coatings Facilitate Attachment of Antimicrobial Peptidomimetics with Broad-Spectrum Antibacterial Activity.

The prevention and treatment of biofilm-mediated infections remains an unmet clinical need for medical devices. With the increasing prevalence of antibiotic-resistant infections, it is important that novel approaches are developed to prevent biofilms forming on implantable medical devices. This study presents a versatile and simple polydopamine surface coating technique for medical devices, using a new class of antibiotics—antimicrobial peptidomimetics. Their unique mechanism of action primes them for activity against antibiotic-resistant bacteria and makes them suitable for covalent attachment to medical devices. This study assesses the anti-biofilm activity of peptidomimetics, characterises the surface chemistry of peptidomimetic coatings, quantifies the antibacterial activity of coated surfaces and assesses the biocompatibility of these coated materials. X-ray photoelectron spectroscopy and water contact angle measurements were used to confirm the chemical modification of coated surfaces. The antibacterial activity of surfaces was quantified for S. aureus, E. coli and P. aeruginosa, with all peptidomimetic coatings showing the complete eradication of S. aureus on surfaces and variable activity for Gram-negative bacteria. Scanning electron microscopy confirmed the membrane disruption mechanism of peptidomimetic coatings against E. coli. Furthermore, peptidomimetic surfaces did not lyse red blood cells, which suggests these surfaces may be biocompatible with biological fluids such as blood. Overall, this study provides a simple and effective antibacterial coating strategy that can be applied to biomaterials to reduce biofilm-mediated infections.

Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity.

The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (μM) minimum inhibitory concentrations against wild-type uropathogenic Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. A 2.98 Å resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.

Antibacterial Activities of Micromonospora sp. 2310 Isolated from Marine Sediment, Baru Island, West Kalimantan

The increase in cases of antibiotic resistance and the discoveries cessation of new classes of antibiotics encourages the exploration of various microorganism sources from unique environments to produce antimicrobial compounds. This study aimed to characterize actinobacteria isolated from marine sediment and evaluate the best medium and incubation time for its antibacterial activities. The sediment sample collected from Buru Island, West Kalimantan, was isolated actinobacteria and characterized based on morphological, biochemical, and molecular (16S rRNA gene) approaches. Antibacterial activities were tested using the well-diffusion methods. Twelve suspected colonies were successfully purified. Isolate 2310, which showed a different morphology colony, was close to Micromonospora based on morphological, biochemical, and 16S rRNA gene analysis and called Micromonospora sp. 2310. Extract isolate 2310 prepared from AM medium showed the best medium for antibacterial activities compared with the other media due to activity against 5 of 6 bacteria, namely Staphylococcus aureus ATCC 12600, Bacillus subtilis ATCC 6051, Salmonella enterica ATCC 14028, Escherichia coli ATCC 11775, Pseudomonas aeruginosa ATCC 9721 except Mycobacterium smegmatis ATCC 14468. Therefore, Micromonospora sp. 2310 could be considered a great potential antibacterial producer.

Synthesis and Evaluation of 3-Halobenzo[b]thiophenes as Potential Antibacterial and Antifungal Agents

The global health concern of antimicrobial resistance has harnessed research interest to find new classes of antibiotics to combat disease-causing pathogens. In our studies, 3-halobenzo[b]thiophene derivatives were synthesized and tested for their antimicrobial activities using the broth microdilution susceptibility method. The 3-halo substituted benzo[b]thiophenes were synthesized starting from 2-alkynyl thioanisoles using a convenient electrophilic cyclization methodology that utilizes sodium halides as the source of electrophilic halogens when reacted along with copper(II) sulfate. This environmentally benign methodology is facile, uses ethanol as the solvent, and results in 3-halo substituted benzo[b]thiophene structures in very high yields. The cyclohexanol-substituted 3-chloro and 3-bromobenzo[b]thiophenes resulted in a low MIC of 16 µg/mL against Gram-positive bacteria and yeast. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) properties of the compounds were determined. The compounds with the lowest MIC values showed excellent drug-like properties with no violations to Lipinski, Veber, and Muegge filters. The time-kill curve was obtained for cyclohexanol-substituted 3-chlorobenzo[b]thiophenes against Staphylococcus aureus, which showed fast bactericidal activity at MIC.

Investigate Natural Product Indolmycin and the Synthetically Improved Analogue Toward Antimycobacterial Agents.

Indolmycin (IND) is a microbial natural product that selectively inhibits bacterial tryptophanyl-tRNA synthetase (TrpRS). The tryptophan biosynthesis pathway was recently shown to be an important target for developing new antibacterial agents against Mycobacterium tuberculosis (Mtb). We investigated the antibacterial activity of IND against several mycobacterial model strains. A TrpRS biochemical assay was developed to analyze a library of synthetic IND analogues. The 4″-methylated IND compound, Y-13, showed improved anti-Mtb activity with a minimum inhibitory concentration (MIC) of 1.88 μM (∼0.5 μg/mL). The MIC increased significantly when overexpression of TrpRS was induced in the genetically engineered surrogate M. bovis BCG. The cocrystal structure of Mtb TrpRS complexed with IND and ATP has revealed that the amino acid pocket is in a state between the open form of apo protein and the closed complex with the reaction intermediate. In whole-cell-based experiments, we studied the combination effect of Y-13 paired with different antibacterial agents. We evaluated the killing kinetics, the frequency of resistance to INDs, and the mode of resistance of IND-resistant mycobacteria by genome sequencing. The synergistic interaction of Y-13 with the TrpE allosteric inhibitor, indole propionic acid, suggests that prospective IND analogues could shut down tryptophan biosynthesis and protein biosynthesis in pathogens, leading to a new class of antibiotics. Finally, we discuss a strategy to expand the genome mining of antibiotic-producing microbes specifically for antimycobacterial development.

Mechanism of biotin carboxylase inhibition by ethyl 4-[[2-chloro-5-(phenylcarbamoyl)phenyl]sulphonylamino]benzoate

The rise of antibacterial-resistant bacteria is a major problem in the United States of America and around the world. Millions of patients are infected with antimicrobial resistant bacteria each year. Novel antibacterial agents are needed to combat the growing and present crisis. Acetyl-CoA carboxylase (ACC), the multi-subunit complex which catalyses the first committed step in fatty acid synthesis, is a validated target for antibacterial agents. However, there are at present, no commercially available antibiotics that target ACC. Ethyl 4-[[2-chloro-5-(phenylcarbamoyl)phenyl]sulfonylamino]benzoate (SABA1) is a compound that has been shown to have antibacterial properties against Pseudomonas aeruginosa and Escherichia coli. SABA1 inhibits biotin carboxylase (BC), the enzyme that catalyses the first half reaction of ACC. SABA1 inhibits BC via an atypical mechanism. It binds in the biotin binding site in the presence of ADP. SABA1 represents a potentially new class of antibiotics that can be used to combat the antibacterial resistance crisis.

Discovery of antimicrobial agent targeting tryptophan synthase.

Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development.

Predicting Antimicrobial Activity of Conjugated Oligoelectrolyte Molecules via Machine Learning.

New antibiotics are needed to battle growing antibiotic resistance, but the development process from hit, to lead, and ultimately to a useful drug takes decades. Although progress in molecular property prediction using machine-learning methods has opened up new pathways for aiding the antibiotics development process, many existing solutions rely on large data sets and finding structural similarities to existing antibiotics. Challenges remain in modeling unconventional antibiotic classes that are drawing increasing research attention. In response, we developed an antimicrobial activity prediction model for conjugated oligoelectrolyte molecules, a new class of antibiotics that lacks extensive prior structure-activity relationship studies. Our approach enables us to predict the minimum inhibitory concentration for E. coli K12, with 21 molecular descriptors selected by recursive elimination from a set of 5305 descriptors. This predictive model achieves an R2 of 0.65 with no prior knowledge of the underlying mechanism. We find the molecular representation optimum for the domain is the key to good predictions of antimicrobial activity. In the case of conjugated oligoelectrolytes, a representation reflecting the three-dimensional shape of the molecules is most critical. Although it is demonstrated with a specific example of conjugated oligoelectrolytes, our proposed approach for creating the predictive model can be readily adapted to other novel antibiotic candidate domains.

Predicting drug targets by homology modelling of Pseudomonas aeruginosa proteins of unknown function.

The efficacy of antibiotics to treat bacterial infections declines rapidly due to antibiotic resistance. This problem has stimulated the development of novel antibiotics, but most attempts have failed. Consequently, the idea of mining uncharacterized genes of pathogens to identify potential targets for entirely new classes of antibiotics was proposed. Without knowing the biochemical function of a protein, it is difficult to validate its potential for drug targeting; therefore, the functional characterization of bacterial proteins of unknown function must be accelerated. Here, we present a paradigm for comprehensively predicting the biochemical functions of a large set of proteins encoded by hypothetical genes in human pathogens to identify candidate drug targets. A high-throughput approach based on homology modelling with ten templates per target protein was applied to the set of 2103 P. aeruginosa proteins encoded by hypothetical genes. The >21000 homology modelling results obtained and available biological and biochemical information about several thousand templates were scrutinized to predict the function of reliably modelled proteins of unknown function. This approach resulted in assigning one or often multiple putative functions to hundreds of enzymes, ligand-binding proteins and transporters. New biochemical functions were predicted for 41 proteins whose essential or virulence-related roles in P. aeruginosa were already experimentally demonstrated. Eleven of them were shortlisted as promising drug targets that participate in essential pathways (maintaining genome and cell wall integrity), virulence-related processes (adhesion, cell motility, host recognition) or antibiotic resistance, which are general drug targets. These proteins are conserved in other WHO priority pathogens but not in humans; therefore, they represent high-potential targets for preclinical studies. These and many more biochemical functions assigned to uncharacterized proteins of P. aeruginosa, made available as PaPUF database, may guide the design of experimental screening of inhibitors, which is a crucial step towards the validation of the highest-potential targets for the development of novel drugs against P. aeruginosa and other high-priority pathogens.

Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens

AbstractWe need new treatment options to control bacterial infections. Bacteria use several strategies to resist drug treatment, including modification of the drug target, and adaptation to a different lifestyle, such as intracellular niches within host cells. Drugs that act on diverse targets are less likely to induce resistance in bacteria, than current antibiotics acting on a single molecular target. Antimicrobial peptides have been explored as a new class of antibiotics because they selectively kill bacteria via a mechanism that involves recognition of the negatively charged microbial surface. Furthermore, antimicrobial peptides with cell‐penetrating properties can cross host cell membranes and target bacteria in the cytosol or sequestered in vesicles. Therefore, bacteria in intracellular niches are less capable of evading treatment and the likelihood of establishing drug resistance is further reduced. This review highlights the potential of antimicrobial peptides as alternative therapeutics to target bacterial pathogens in both extracellular and intracellular environments, and to avoid acquired drug‐resistance.