Explor Drug Sci EDS Exploration of Drug Science 2836-7677 Open Exploration Publishing 10.37349/eds.2025.100887 100887 Review Combating antibiotic resistance: mechanisms, challenges, and innovative approaches in antibacterial drug development Rajesh Aiswarya M. Conceptualization Investigation Writing—original draft Writing—review & editing 1 Pawar Shraddha Subhash Conceptualization Investigation Writing—original draft Writing—review & editing 1 https://orcid.org/0000-0001-9994-7883 Doriya Kruthi Validation Writing—review & editing Supervision 2 * https://orcid.org/0000-0002-2764-782X Dandela Rambabu Validation Writing—review & editing Supervision 1 * Sabatier Jean-Marc Academic Editor Aix-Marseille University, France 1Department of Chemistry, Institute of Chemical Technology-IndianOil Odisha Campus, Bhubaneswar 751013, Odisha, India 2Department of Chemical Engineering, Institute of Chemical Technology-IndianOil Odisha Campus, Bhubaneswar 751013, Odisha, India *Correspondence: Rambabu Dandela, Department of Chemistry, Institute of Chemical Technology-IndianOil Odisha Campus, Bhubaneswar 751013, Odisha, India. r.dandela@iocb.ictmumbai.edu.in Kruthi Doriya, Department of Chemical Engineering, Institute of Chemical Technology-IndianOil Odisha Campus, Bhubaneswar 751013, Odisha, India. k.doriya@iocb.ictmumbai.edu.in 2025 26 01 2025 3 100887 04 11 2024 27 12 2024 © The Author(s) 2025. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Antibiotic resistance is a significant threat to public health and drug development, driven largely by the overuse and misuse of antibiotics in medical and agricultural settings. As bacteria adapt to evade current drugs, managing bacterial infections has become increasingly challenging, leading to prolonged illnesses, higher healthcare costs, and increased mortality. This review explores the critical role of antibiotics in fighting infections and the mechanisms that enable bacteria to resist them. Key antibiotics discussed include carvacrol, dalbavancin, quinolones, fluoroquinolones, and zoliflodacin, each with unique actions against bacterial pathogens. Bacteria have evolved complex resistance strategies, such as enzyme production to neutralize drugs, modifying drug targets, and using efflux pumps to remove antibiotics, significantly reducing drug efficacy. Additionally, the review examines the challenges in antibiotic development, including a declining discovery rate of novel drugs due to high costs and regulatory complexities. Innovative approaches, such as structure-based drug design, combination therapies, and new delivery systems, are highlighted for their potential to create compounds with enhanced action against resistant strains. This review provides valuable insights for researchers and developers aiming to combat antibiotic resistance and advance the development of robust antibacterial therapies for future health security.

Structure-based strategies to combat antibiotic resistance in bacterial infections

Antimicrobial resistance drug development antibacterial therapies resistance mechanism Introduction

Antibacterial medications are essential for treating bacterial infections, significantly reducing mortality and morbidity [1]. However, the rising threat of antimicrobial resistance (AMR) poses a challenge to public health by complicating treatment, increasing healthcare costs, and limiting therapeutic options [2]. This review examines the critical role of antibacterial drugs in managing infections and the urgent challenges posed by AMR. Antibacterial drugs operate by targeting crucial bacterial functions, such as cell wall and protein synthesis, to either inhibit growth or destroy bacterial cells [3]. Major antibiotic classes including penicillins, tetracyclines, and fluoroquinolones are commonly employed against infections like salmonellosis and tuberculosis [4]. However, the effectiveness of these treatments is significantly hindered by bacterial resistance mechanisms, such as antibiotic modification and target alteration.

The misuse of antibiotics in healthcare and agriculture has accelerated the development and spread of drug-resistant pathogens [5]. For instance, research has identified that resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae are particularly prevalent in hospital settings [6]. Additionally, antibiotics exposure impacts the environmental microbial populations, potentially affecting ecosystem dynamics and effecting human health [7].

The World Health Organization (WHO) has called for urgent action to address the spread of antibiotic resistance [8]. Efforts such as antibiotic stewardship programs and biotechnological innovations are being pursued to address resistant strains like methicillin-resistant Staphylococcus aureus (MRSA) [9]. The increasing prevalence of resistant strains, particularly in opportunistic pathogens like S. aureus, emphasizes the need for novel infection control approaches.

Antibiotic resistance, driven by misuse and bacterial adaptations, poses a latent pandemic threat by fostering multidrug-resistant infections and outpacing the development of new treatments [10–12]. In 2019, an estimated 1.27 million people died directly from AMR worldwide [13]. To address these challenges, researchers are exploring biotechnological innovations such as micro-/nano-bioplatforms, bacteriophage therapies, and CRISPR-based antimicrobials as promising alternatives to conventional antibiotics. Table 1 outlines key antimicrobial drugs and their respective target microbes, emphasizing the pressing need to address resistance mechanisms.

Antimicrobial drugs with their mechanism of action

S. No. Antimicrobial drugs Use Target microbe References
1 Antisense phosphorothioate oligonucleotide Helps fluoroquinolone-resistant Escherichia coli regain antibiotic sensitivity by targeting acrB gene Escherichia coli [14]
2 Amikacin Effective against bacterial infections Mycobacterium and Pseudomonas aeruginosa [15]
3 Vancomycin and linezolid Used to treat complex skin and soft-tissue infections brought on by methicillin-resistant Staphylococcus aureus (MRSA) as well as nosocomial pneumonia Staphylococcus aureus [16]
4 Penicillin G procaine and pirlimycin Used for treating mastitis in lactating cows Mycoplasma spp. and Streptococcus agalactiae [17]
5 Silica-based biomaterials loaded with ferulic acid Used in bone tissue engineering to promote bone graft healing and stop bacterial infections Staphylococcus aureus and E. coli [18]
6 Non-canonical amino acids (NCAAs) Plays a role in designing antimicrobial peptides to combat multidrug-resistant bacteria Gram-positive and Gram-negative bacteria [19]
7 Ciprofloxacin This medication is a component of a new thermo-responsive hydrogel formulation intended for drug-eluting uses Gram-negative bacteria [20]
8 Taromycin A and Gassericin A Exhibit binding mechanism by interacting with Lys 234 Antibiotic resistant bacteria that produce TEM-1 β-lactamases [21]

Resistant bacteria use various mechanisms, including drug target modification, biofilm formation, and efflux pump activation, while the genetic transfer of resistance genes promotes their survival in antibiotic-rich environments [9, 22, 23]. The Global Antimicrobial Resistance and Use Surveillance System (GLASS) further highlights the increasing burden of diseases caused by resistant microorganisms worldwide [24].

This review highlights the essential role of antibacterial drugs in managing infections and the urgent challenge posed by AMR. It also explore emerging strategies, including nanotechnology and bacteriophage therapy, that show promise in targeting resistant strains effectively [25]. Additionally, this work also discusses antibiotic classifications, mechanisms, bacterial resistance strategies, and best practices for developing effective antibiotics.

 History of antibiotic and emergence of resistance

Historically, antibiotics transformed infectious disease management, but bacteria quickly developed resistance. During the “Golden Age” of antibiotic discovery (1930s–1980s), key classes such as β-lactams and aminoglycosides were introduced, yet bacterial resistance soon followed [26]. The widespread application of antibiotics by humans has caused resistant bacteria to emerge, exacerbating the long-standing issue of antibiotic resistance [27]. Complicating treatment efforts is the discovery of novel resistance mechanisms brought about by the transition from focusing on planktonic bacteria to comprehending biofilm networks [28].

Key historical milestones:

1928—Penicillin’s discovery, which initiated the development of contemporary antibiotics [29].

1942—Emergence of bacterial resistance to penicillin [29].

1980 to present—A complete shift towards the production of semi-synthetic antibiotics but a decline in new classes [30].

The arms race between bacteria and antibiotics endures, as evidenced by ancient antibiotic resistance genes (ARGs) even in pristine environments, indicating longstanding bacterial adaptation [31]. The use of antibiotics in agricultural contexts has resulted in the selection of resistant strains, which has complicated the resistance landscape [32].

 Principle and classification of antibacterial drugs

Antimicrobial drugs work by focusing on particular bacterial functions, including DNA replication, protein synthesis, and cell wall construction. Their spectrum ranges from broad to narrow, and they may encounter bacterial resistance via efflux pumps or enzyme degradation. Drug efficacy and dosage are determined by pharmacokinetics and pharmacodynamics, whereas pharmacogenomics customizes therapies according to genetic variables. Combination treatments reduce resistance and increase efficacy. To reduce adverse effects and fight resistance, antibiotic stewardship and appropriate therapeutic use including targeted and empirical therapy are essential [33]. Antibacterial agents are categorized into five main groups: sources, type of action, function, chemical structure, and spectrum of activity.

On the basis of sources Natural

Antibacterial drugs can be derived from natural sources such as plants, animals, and microorganisms. Some of the examples of naturally occurring antibacterial agents and their mechanisms of action are shown in Table 2 [34].

Some of the examples of naturally occurring antibacterial agents and their mechanisms of action

Naturally occurring antibacterial drugs Mechanism of action Reference
Trans-cinnamaldehyde Inhibits the growth of multidrug-resistant Escherichia coli by disrupting the cell wall integrity, leading to cell lysis and death. [35]
Carvacrol Damages bacterial cell membranes, prevents biofilm formation, and disrupts quorum sensing, making it effective against multidrug-resistant strains. [36]
Gentisaldehyde Alkylates essential cellular components such as DNA, RNA, and proteins, resulting in protein denaturation and alteration of nucleic acids, which interferes with bacterial function. [37]
Phloroglucinaldehyde Uses a dual mechanism by disrupting bacterial cell membranes and inhibiting essential metabolic pathways critical for bacterial survival. [38]
Semi‐synthetic antibacterials

Semi-synthetic antibacterials are chemically modified derivatives of natural antibiotics, aimed at enhancing efficacy and properties.​ Some of the semi-synthetic antibacterials with their mechanism of action are shown in Table 3 [34].

List of semi-synthetic antibacterial agents with their mechanisms of action

Semi-synthetic antibacterials Mechanism of action Reference
Ceftaroline Binds to penicillin-binding proteins, disrupts cell wall synthesis and cross-linking, leading to weakened cell walls, bacterial lysis, and cell death. [39]
Dalbavancin Inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan chains, disrupting transpeptidation, which results in a weakened cell wall and bacterial lysis. [40]
Oritavancin Utilizes three mechanisms: i) inhibition of transglycosylation, ii) inhibition of transpeptidation, and iii) disruption of bacterial cell membrane. [41]
Synthetic antibacterials

​Synthetic antibacterials are artificially created compounds designed to inhibit or kill bacteria.​ Table 4 gives some of the examples of synthetic antibacterials with their mechanism of action [34].

List of synthetic antibacterial agents with their mechanisms of action

Synthetic antibacterials Mechanism of action Reference
Cresomycin Binds strongly to its ribosomal target, blocking protein synthesis more effectively than other antibiotics. [42]
Iboxamycin (IBX) Targets bacterial ribosomes, disrupting protein synthesis in both Gram-positive and Gram-negative bacteria, making it effective for multidrug-resistant infections. [43]
Oxepanoprolinamide Interferes with ribosomal function sites to halt bacterial growth and proliferation, effectively stopping protein synthesis and leading to cell death. [44]
Type of action Bacteriostatic

The term “bacteriostatic” refers to substances that impede or prevent the growth of bacteria. Bacteriostatic antibacterials function by inhibiting the growth and replication of bacteria through various mechanisms. For example, sulphonamides act by blocking the early stages of folate synthesis, which is essential for bacterial DNA replication and cell growth [45]. Additionally, amphenicols prevent bacterial cells from the protein synthesis. They accomplish this function by attaching themselves to the bacterial ribosome’s 50S subunit and blocking the creation of peptide bonds during the translation process. In the end, this prevents bacterial growth and replication by interfering with the creation of vital proteins [46]. Furthermore, spectinomycin binds to the 30S ribosomal subunit, disrupting protein synthesis, and thereby hindering bacterial growth [47]. Lastly, trimethoprim interferes with the tetrahydrofolate synthesis pathway, which is crucial for DNA and protein synthesis in bacteria [48]. Each of these agents uses a distinct mechanism to prevent bacterial proliferation without directly killing the organisms.

 Bactericidal

Bactericidal agents work by destroying bacterial cell walls or membranes, leading to bacterial death. Examples include penicillin and quinolones, such as levofloxacin and ciprofloxacin. For instance, carbapenems interfere with bacterial cell wall formation, leading to cell lysis and death [49]. Gentamicin blocks protein production, which is essential for bacterial survival [50]. Quinolones and fluoroquinolones inhibit bacterial DNA replication, preventing the cell from reproducing and leading to bacterial death [51]. Lastly, vancomycin disrupts cell wall construction, which weakens the bacterial cell structure and ultimately causes cell death [52]. Each of these agents targets a specific bacterial function, effectively eliminating the organisms.

 Chemical structure Group A (β‐lactams)

This category includes β-lactam antibiotics such as penicillin derivatives, cephalosporins, monobactams, and carbapenems. Figure 1 gives bacterial activity, mechanism of action, and resistance group A (β‐lactams) [53].

Presents bacterial activity, mechanism of action, and resistance for group A (β-lactams) and group B (Aminoglycosides)

Group B (Aminoglycosides)

Aminoglycosides, including streptomycin, gentamicin, sisomicin, netilmicin, and kanamycin, work by binding to bacterial ribosomes, disrupting protein synthesis, and inhibiting bacterial growth. Figure 1 gives bacterial activity, mechanism of action, and resistance group B (Aminoglycosides) [54].

 Macrolides

A macrocyclic lactone ring with changeable side chains is a characteristic of macrolides by attaching themselves to the bacterial 50S ribosomal subunit, they prevent the production of proteins [55, 56]. Erythromycin, azithromycin, and clarithromycin are notable macrolides that are efficient against intracellular infections and have broad-spectrum action [57].

 Tetracyclines

Tetracyclines are distinguished by their four rings by attaching to the 30S ribosomal subunit and blocking the attachment of aminoacyl-tRNA, they inhibit the production of proteins [58]. Tetracyclines perform well against a variety of atypical infections including Gram-positive and Gram-negative bacteria [59].

 Quinolones

Quinolones have a bicyclic ring structure that is frequently fluorine-modified [60]. They interfere with DNA replication by targeting bacterial gyrase and topoisomerase IV [61]. Because of their broad-spectrum activity and good tissue penetration, fluoroquinolones such as ciprofloxacin and moxifloxacin are used extensively [62, 63].

 Sulfonamides

Consists of an aromatic amine with a sulfonamide group attached. It inhibits dihydropteroate synthase, preventing the production of folate, which is necessary for bacterial development. Commonly used sulfonamides in clinical settings include sulfadiazine and sulfamethoxazole [64].

 Glycopeptides

Vancomycin and teicoplanin are well-known glycopeptide antibiotics (GPAs) used as last-resort treatments for severe infections [65]. They are distinguished by a heptapeptide backbone with numerous modifications, such as glycosylation and chlorination [66]. They bind to lipid II, disrupting the synthesis of bacterial cell walls, and are especially effective against resistant strains [67].

 Functions

Antibiotics target essential bacterial processes such as cell wall synthesis, membrane function, protein synthesis, and nucleic acid synthesis. They can be categorized into four groups based on their mode of action: cell wall synthesis inhibitors, membrane function inhibitors, protein synthesis inhibitors, and nucleic acid synthesis inhibitors. Understanding these functions is crucial for determining how each antibacterial works. Each of these groups will be discussed briefly in the following sections [68].

Cell wall synthesis inhibitors

The bacterial cell wall, primarily composed of peptidoglycan, is crucial for structural integrity, making its synthesis a key target for antibiotics known as cell wall synthesis inhibitors. β-Lactam drugs, such as penicillin and cephalosporins, inhibit peptidoglycan synthesis by binding to penicillin-binding proteins, leading to bacterial lysis. Gram-positive and Gram-negative bacteria exhibit varying susceptibility to these drugs due to differences in their cell wall structures and the presence of β-lactamases that confer resistance [69].

 Inhibitors of membrane function

Polymyxins are cyclic peptide antibacterial agents that selectively target the outer membrane of Gram-negative bacteria by disrupting their membrane structure and increasing permeability, leading to cell death. They are effective against Gram-negative bacteria due to their affinity for lipopolysaccharides, but have little to no effect on Gram-positive bacteria due to their thick cell walls. Therapeutically, polymyxins B and E are commonly used in chemotherapy [70].

 Protein synthesis inhibitors

Protein synthesis inhibitors are antibiotics that target bacterial protein synthesis to treat infections, taking advantage of the slower protein synthesis in human cells to minimize side effects. These inhibitors disrupt various stages of protein synthesis, including initiation, elongation, and termination. While toxicity and resistance are concerns, the selective targeting of bacterial processes makes these drugs effective [71].

 Inhibition of nucleic acid synthesis

Nucleic acid synthesis inhibitors are antibiotics targeting bacterial DNA and RNA synthesis, leveraging differences in prokaryotic and eukaryotic enzymes for selective toxicity. RNA inhibitors, like rifampin, block transcription by binding to RNA polymerase, while DNA inhibitors, such as quinolones, inhibit DNA gyrase, disrupting DNA replication. Other drugs, like nitrofurantoin and metronidazole, target anaerobic bacteria by damaging DNA strands. This disruption of nucleic acid synthesis ultimately leads to bacterial cell death [72].

 Spectrum activity Narrow spectrum antibacterials

Narrow spectrum antibacterials have a limited range of action, targeting either Gram-positive or Gram-negative bacteria specifically. These agents typically face less bacterial resistance. Table 5 provides the list of narrow spectrum antibacterials includes, methicillin, nafcillin, oxacillin, temocillin, and cloxacillin (dicloxacillin, flucloxacillin) [73].

Examples of narrow spectrum antibacterials with their binding site function

Narrow spectrum antibacterial Binding site function References
Methicillin Competitively blocking the transpeptidase enzyme, which is a type of penicillin-binding proteins (PBPs). [74]
Nafcillin Specifically targets PBPs essential for cell wall synthesis, aiding in cross-linking peptidoglycan for wall rigidity. [75]
Oxacillin The binding site is shaped by loops near helix 5, affecting substrate affinity; variants like OXA-2 and OXA-51 bind better to carbapenems. [76]
Cloxacillin Binds to serum albumin through hydrophobic interactions, with a 1:1 stoichiometry, as indicated by fluorescence spectroscopy studies. [77]
Broad spectrum antibacterial

Broad spectrum antibacterials target a wide range of pathogenic bacteria, including both Gram-positive and Gram-negative strains. Table 6 lists broad spectrum antibacterials include ampicillin, quinolones such as maxaquin (lomefloxacin), floxin (ofloxacin), noroxin (norfloxacin), tequin (gatifloxacin), cipro (ciprofloxacin), avelox (moxifloxacin), levaquin (levofloxacin), factive (gemifloxacin), and carbapenems [78].

Broad spectrum antibacterials with their binding site function

Broad spectrum antibacterial Binding site function References
Quinolones Inhibit DNA replication by binding to DNA gyrase and topoisomerase IV. [43]
Carbapenems Inhibit cell wall synthesis by binding to penicillin-binding proteins. [49]
Antibacterial resistance

AMR refers to the ability of bacteria to survive and proliferate even in the presence of antibiotics, posing a significant threat to global public health [79, 80]. Bacteria can develop resistance through either intrinsic mechanisms (naturally possessed traits) or acquired mechanisms (through transformation, transduction, or conjugation of mobile genetic elements like transposons and plasmids). There are two main types of antibacterial resistance: natural antibacterial resistance, also known as intrinsic resistance, occurs naturally within a bacterial species without the involvement of horizontal gene transfer. In this case, bacteria inherently possess resistance traits, and they may express their resistance genes only when exposed to antibiotics. On the other hand, acquired antibacterial resistance develops when bacteria obtain resistance traits through horizontal gene transfer, acquiring genetic material from other bacteria. This form of resistance can also arise from mutations in the cell’s DNA during replication, which may enhance bacterial survival against antibiotic treatments [81–83].

Mechanism of antibacterial resistance

AMR complicates infection treatment through mechanisms such as reduced intracellular antibiotic concentration, antibiotic inactivation, and target site alteration. Efflux pumps and decreased cell permeability limit antibiotic entry, while enzymatic degradation (e.g., β-lactamases) and chemical modifications (phosphorylation, adenylation, acetylation) inactivate antibiotics. Target site mutations and modifications further reduce antibiotic binding, as seen with resistance to tetracyclines and macrolides. Combating antibacterial resistance requires a multimodal approach involving stringent antibiotic stewardship, combination therapies, and novel drug development (Figure 2) [79].

Mechanism of antibacterial resistance

Spread of antimicrobial resistance

The spread of AMR can be attributed to several key factors: human practices, such as the overuse and misuse of antimicrobials, poor infection control, and limited public awareness; animal-related practices, including the extensive use of antibiotics in livestock and aquaculture, leading to transmission through food chains and direct contact; environmental factors, such as the release of antibiotics and resistant bacteria into water sources; and wildlife-related factors, with transmission occurring through contact with wildlife and increased habitat encroachment [84].

 Discovery and development of novel drugs

Recent advancements in the discovery and development of novel therapeutics such as phage therapy, antimicrobial peptides (AMPs), CRISPR-Cas9, combination therapies, repurposing existing drugs, and in silico drug design have shown significant promise across various medical fields are explained below.

Phage therapy

Phage therapy offers a promising alternative to antibiotics, particularly against antimicrobial-resistant bacteria. It targets pathogenic bacteria with high specificity, preserving beneficial microbiota. Success stories and the establishment of phage banks and dedicated centers are enhancing personalized treatments and outcomes [85].

 Antimicrobial peptides

AMPs are a promising class of agents with broad spectrum activity against antibiotic-resistant infections. Recent research focuses on optimizing AMPs for better stability and efficacy, with successful clinical trials treating skin infections and resistant strains. AMPs show potential as alternatives to conventional antibiotics [86].

 CRISPR-Cas9

The CRISPR-Cas9 system enables precise targeting of antibiotic resistance genes in bacteria. Phage-mediated delivery allows effective gene editing, sensitizing bacteria to treatment. This technology shows promise for both therapy and advancing microbial genetics [87].

 Combination therapies

Combination therapies that integrate antibiotics with phage therapy or AMPs enhance treatment outcomes against resistant infections by improving efficacy and reducing dosages. Research indicates that these combinations can successfully treat chronic infections, yielding higher success rates than single therapies. This synergistic approach underscores the importance of developing comprehensive strategies to optimize patient care [88].

 Repurposing existing drugs

Repurposing existing drugs, such as anticancer drugs like imatinib and statins, shows promise in combating antibiotic-resistant bacteria. This approach utilizes existing safety data, speeding up the development of new treatments. Ongoing research into drug mechanisms aids in identifying potential repurposing candidates [89].

 In silico drug design

In silico drug design uses computational tools and machine learning to accelerate the discovery of new antibacterial agents. Recent AI advancements improve the prediction of antimicrobial activity and the identification of potential drug candidates. Integrating in silico methods with traditional approaches enhances the efficiency of developing treatments for multidrug-resistant pathogens [90].

In oncology, anticancer peptides (ACPs) show promising potential for breast cancer therapy. Notably, lactoferricin B (LfcinB) and its derivatives exhibit cytotoxic effects against various breast cancer cell lines. Enhancing palindromic peptides, such as RWQWRWQWR, improves cancer cell selectivity and inhibits cell migration, thereby progressing the preclinical phase of drug discovery [91]. Additionally, the integration of non-canonical amino acids (NCAAs) into peptide designs has drawn significant interest in medicinal chemistry, enhancing hydrophobicity and bioactivity, especially for antimicrobial peptides targeting multi-drug-resistant bacteria. Systematic exploration of modified peptides through cheminformatics enables the creation of compounds with improved stability and efficacy for therapeutic use [19]. In cardiovascular therapy, atherosclerosis treatment, ground-breaking treatments are emerging. Inclisiran, a pioneering small interfering RNA (siRNA) drug, reduces low-density lipoprotein (LDL) cholesterol by inhibiting PCSK9, providing a viable option for patients unresponsive to statins. Furthermore, histone deacetylase (HDAC) inhibitors, including TMP195, RGFP966, and MC1569, target key pathways in inflammation and lipid metabolism, addressing the underlying causes of vascular aging and atherosclerosis [92]. These innovative approaches underline the potential of multi-target therapies in tackling complex diseases.

The COVID-19 pandemic has accelerated the repurposing of FDA-approved drugs for potential effectiveness against SARS-CoV-2. Key candidates include dexamethasone, hydroxychloroquine, remdesivir, and favipiravir. Originally developed for Ebola, remdesivir inhibits viral RNA polymerase, blocking replication, while favipiravir, initially approved for influenza, also prevents viral RNA production. Hydroxychloroquine has been investigated for its ability to block viral entry and modulate immune responses, and dexamethasone has shown mortality reduction in severe COVID-19 cases by dampening hyper-inflammatory reactions [93].

Natural products are also being re-evaluated for therapeutic use. Curcumin, despite its low availability, continues to gain attention for anticancer therapy, spurring research on improved formulations. Microbial metabolites have also emerged as promising candidates in cancer therapy, with compounds like bortezomib demonstrating efficacy by targeting proteasomal pathways Figure 3 [94]. These developments highlight the importance of exploring multiple pathways in drug discovery. Some of the examples of antibacterial drugs along with their mechanism of action are mentioned in Table 7. This table highlights the ongoing challenges in combating bacterial resistance, emphasizing the need for continuous innovation in antibiotic development.

Structure of microbial metabolites that are clinically used for cancer chemotherapy

The search for natural compounds to treat age-related diseases increasingly focuses on senolytics like dasatinib and quercetin. Originally developed for leukemia, dasatinib effectively targets and eliminates senescent cells, while quercetin, a flavonoid, promotes autophagy and reduces the senescence-associated secretory phenotype (SASP). Additionally, resveratrol and fisetin support healthy aging by activating sirtuins, enhancing autophagy, and selectively removing senescent cells. Compounds like cyclo-trijuglone, derived from traditional herbs, highlight the potential of blending traditional knowledge with modern pharmacology to develop new age-related therapeutics [95]. The synergy of natural compounds and advanced pharmacological strategies holds promise for tackling both age-related diseases and bacterial resistance.

List of antibacterial drugs

S. No. Structure Drug Mechanism of action Mechanism of resistance References
1 Tedizolid Binds to 23S rRNA in the 50S ribosomal subunit, blocking protein synthesis initiation and aminoacyl-tRNA binding in bacteria. Resistance arises through 23S rRNA mutations or cfr gene transfer, reducing the drug’s ribosomal binding affinity. [96]
2 Ceftolozane-tazobactam Combines bactericidal effects of ceftolozane with tazobactam’s β-lactamase inhibition. Resistance involves metallo-β-lactamases and AmpC hyperproduction, reducing drug efficacy. [97]
3 Oritavancin Inhibits peptidoglycan synthesis by binding to D-Ala-D-Ala and D-Ala-D-Lac, blocking transglycosylation and transpeptidation. Resistance due to changes in VanB operon expression or D-Lac precursor presence, which reduce drug sensitivity. [98]
4 Ceftazidime-Avibactam Ceftazidime disrupts cell wall synthesis via penicillin-binding proteins (PBPs); avibactam inhibits ceftazidime breakdown by β-lactamases. Resistance stems from metallo-β-lactamases, specific class D enzymes, mutations in β-lactamase enzymes (e.g., KPC-3), along with reduced permeability and efflux. [99]
5 Meropenem Inhibits cell wall synthesis by binding to PBPs; vaborbactam enhances efficacy by inhibiting class A β-lactamases. Resistance mechanisms include class B and D carbapenemases, altered PBPs, and increased efflux pump activity. [100]
6 Pretomanid In anaerobic conditions, generates reactive intermediates that inhibit respiration in non-replicating bacteria and disrupt protein and lipid synthesis in replicating bacteria. Resistance primarily occurs through mutations in activation-related genes (e.g., Ddn, Fgd, fbiA/B/C), sometimes affecting CofC or rplC and conferring dual resistance with linezolid. [101]
7 Lefamulin Binds to the 50S ribosomal subunit, inhibiting peptide bond formation and protein synthesis in bacteria. Resistance arises from genes like vga(A), cfr, and mutations in 23S rRNA and ribosomal proteins (rplC, rplD). [102]
8 Sarecycline Binds to the bacterial ribosome’s A site, blocking mRNA translation; also reduces inflammation by suppressing cytokines and neutrophil activation. Resistance occurs through degradation, rRNA mutations, ribosomal protection (e.g., TetM, TetO), and efflux pumps like TetA. [103]
9 Plazomicin Inhibits protein synthesis by binding to the A-site of 16S rRNA in the 30S ribosomal subunit in Gram-negative bacteria. Resistance is mostly due to aminoglycoside-modifying enzymes (AMEs), target site alterations, and changes in porin or efflux pump expression. [104]
10 Halicin Exhibits broad-spectrum antibacterial action by damaging DNA and disrupting the proton motive force (PMF), impeding bacterial adaptation and resistance. Resistance is rare and mainly involves mutations affecting protein synthesis, transport, and nitroreduction. [105]
11 Zoliflodacin Inhibits bacterial type 2 topoisomerase, primarily targeting DNA gyrase, preventing fluoroquinolone cross-resistance and double-strand DNA breaks. Resistance is uncommon, associated with gyrB gene alterations, and presents minimal cross-resistance with other antibiotics. [106]
12 Durlobactam Restores Acinetobacter baumannii’s susceptibility to sulbactam by inhibiting class D carbapenemases, β-lactamases, and reducing PBP2. Resistance may occur through metallo-β-lactamases, certain PBP mutations, and the AdeIJK efflux system. [107]
13 Opelconazole Inhibits 14-α-demethylase (CYP51A), blocking ergosterol formation in fungal cell membranes, effective against Aspergillus and Mucorales. Resistance primarily arises from ERG11 gene mutations, notably TR34/L98H in cyp51A, which reduce drug binding efficacy. [108]
Conclusions

This review has highlighted the critical importance of antibacterial drugs in combating infections and the growing threat posed by AMR. It covers the history and evolution of antibiotics, tracing their journey from the discovery of penicillin to the current era of semi-synthetic and synthetic antibacterials. The classification of antibacterial drugs is discussed based on their sources, mechanisms of action, chemical structures, and spectrum of activity. The mechanisms of antibacterial resistance, including intrinsic and acquired strategies employed by bacteria, are examined alongside factors contributing to the spread of resistance, such as the overuse of antibiotics in healthcare and agriculture. The review also highlights recent advances in drug discovery and development, including innovative approaches such as the use of NCAAs, repurposing existing drugs, and exploring natural products. Additionally, examples of new antibacterial agents are presented, along with insights into their mechanisms of action and emerging resistance patterns.

The increasing prevalence of resistant bacterial strains underscores the urgent need for continued innovation in antibiotic development. Multi-faceted approaches combining traditional and cutting-edge strategies show promise for addressing this global health threat. Key priorities include developing robust models to evaluate new antimicrobial agents and exploring combination therapies to combat resistance. Further, improving antibiotic stewardship in healthcare and agriculture and investigating alternative therapeutic approaches like bacteriophage therapy. Hence, by pursuing these priorities through collaborative, cross-disciplinary efforts, the scientific and medical communities can work to stay ahead of evolving bacterial resistance and ensure effective treatments remain available for future generations. Continued research, innovation, and responsible antibiotic use will be critical in preserving the efficacy of these life-saving drugs.

 Abbreviations AMPs

antimicrobial peptides

 AMR

antimicrobial resistance

 NCAAs

non-canonical amino acids

 Declarations Author contributions

AMR and SSP: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. KD and RD: Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

 Conflicts of interest

The authors declare that they have no conflicts of interest.

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 Consent to participate

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 Consent to publication

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 Availability of data and materials

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 Laxminarayan R Matsoso P Pant S Brower C Røttingen J Klugman K et al. Access to effective antimicrobials: a worldwide challenge Lancet 2016 387 168 75 10.1016/S0140-6736(15)00474-2 26603918 Ferri M Ranucci E Romagnoli P Giaccone V Antimicrobial resistance: A global emerging threat to public health systems Crit Rev Food Sci Nutr 2017 57 2857 76 10.1080/10408398.2015.1077192 26464037 Ombašić A An Insight into Antibiotic Resistance Mechanisms: Microbiological Implications for Public Health Bulgarian Society for Microbiology (Union of Scientists in Bulgaria) 2024 40 131 41 10.59393/amb24400201 Sheikh BA Bhat BA Mir MA Antimicrobial resistance: new insights and therapeutic implications Appl Microbiol Biotechnol 2022 106 6427 40 10.1007/s00253-022-12175-8 36121484 Singh B Bhat A Ravi K Antibiotics Misuse and Antimicrobial Resistance Development in Agriculture: A Global Challenge Environ Health (Wash) 2024 2 618 22 10.1021/envhealth.4c00094 39512391 PMC11540112 de Carvalho JJV Boaventura FG de Cássia Ribeiro da Silva A Ximenes RL Rodrigues LKC de Almeida Nunes DA et al. Bactérias multirresistentes e seus impactos na saúde pública: Uma responsabilidade social Research, Society and Development 2021 10 e58810616303 10.33448/rsd-v10i6.16303 Pinto I Simões M Gomes IB An Overview of the Impact of Pharmaceuticals on Aquatic Microbial Communities Antibiotics (Basel) 2022 11 1700 10.3390/antibiotics11121700 36551357 PMC9774725 Bulathsinhala BKS Siriwardana RC Liyanage CAH Acute portal vein thrombosis leading to small bowel stricture Sri Lanka Journal of Surgery 2017 35 14 10.4038/sljs.v35i3.8415 Salam MA Al-Amin MY Salam MT Pawar JS Akhter N Rabaan AA et al. Antimicrobial Resistance: A Growing Serious Threat for Global Public Health Healthcare (Basel) 2023 11 1946 10.3390/healthcare11131946 37444780 PMC10340576 Jha KK Saini S Raj A Bishnoi H The Antibiotic Resistance Crisis Asian Journal of Pharmaceutical Research and Development 2023 11 44 52 10.22270/ajprd.v11i5.1321 Venkatasubramanian A Veluchamy C Chandrasekaran R Thiagarajan K Urgent imperatives and perspectives of Antimicrobial resistance Res J Biotechnol 2023 18 255 63 10.25303/1810rjbt2550263 Muteeb G Rehman MT Shahwan M Aatif M Origin of Antibiotics and Antibiotic Resistance, and Their Impacts on Drug Development: A Narrative Review Pharmaceuticals (Basel) 2023 16 1615 10.3390/ph16111615 38004480 PMC10675245 Rolfe RJ Shaikh H Tillekeratne LG Mass drug administration of antibacterials: weighing the evidence regarding benefits and risks Infect Dis Poverty 2022 11 77 10.1186/s40249-022-00998-6 35773722 PMC9243730 Moreira L Guimarães NM Santos RS Loureiro JA Pereira MC Azevedo NF Promising strategies employing nucleic acids as antimicrobial drugs Mol Ther Nucleic Acids 2024 35 102122 10.1016/j.omtn.2024.102122 38333674 PMC10850860 Arslan B Vasudeva G Hirsch EB Public-Private and Private-Private Collaboration as Pathways for Socially Beneficial Innovation: Evidence from Antimicrobial Drug-Development Tasks Academy of Management Journal 2024 67 554 82 10.5465/amj.2021.1260 Geilen J Kainz M Zapletal B Naka A Tichy J Jäger W et al. Antimicrobial Drug Penetration Is Enhanced by Lung Tissue Inflammation and Injury Am J Respir Crit Care Med 2024 209 829 39 10.1164/rccm.202306-0974OC 38099833 Portillo-Gonzalez R Garzon A Pereira RVV Silva-Del-Rio N Karle BM Habing GG Effect of a dairy farmworker stewardship training program on antimicrobial drug usage in dairy cows J Dairy Sci 2024 107 2941 53 10.3168/jds.2023-23663 38056568 Atkinson I Seciu-Grama A Serafim A Petrescu S Voicescu M Anghel EM et al. Bioinspired 3D scaffolds with antimicrobial, drug delivery, and osteogenic functions for bone regeneration Drug Deliv Transl Res 2024 14 1028 47 10.1007/s13346-023-01448-y 37853275 Viayna A Matamoros P Blázquez-Ruano D Zamora WJ From Canonical to Unique: Extension of A Lipophilicity Scale of Amino Acids to Non-Standard Residues Explor Drug Sci 2024 2 389 407 10.37349/eds.2024.00053 Goudarzi ZM Zaszczyńska A Kowalczyk T Sajkiewicz P Electrospun Antimicrobial Drug Delivery Systems and Hydrogels Used for Wound Dressings Pharmaceutics 2024 16 93 10.3390/pharmaceutics16010093 38258102 PMC10818291 Sowmiya A Jayakodi S Selvam KA Sangeetha K In silico Molecular Docking of Cyclic Peptides against TEM-1 Beta-Lactamases for Effective Antimicrobial Drug Development J Pure Appl Microbiol 2024 18 1674 83 10.22207/jpam.18.3.16 Zhang F Cheng W The Mechanism of Bacterial Resistance and Potential Bacteriostatic Strategies Antibiotics (Basel) 2022 11 1215 10.3390/antibiotics11091215 36139994 PMC9495013 Salimiyan Rizi K Ghazvini K kouhi Noghondar M Adaptive Antibiotic Resistance: Overview and Perspectives Journal of Infectious Diseases & Therapy 2018 6 363 10.4172/2332-0877.1000363 Shinu P Mouslem AKA Nair AB Venugopala KN Attimarad M Singh VA et al. Progress Report: Antimicrobial Drug Discovery in the Resistance Era Pharmaceuticals (Basel) 2022 15 413 10.3390/ph15040413 35455410 PMC9030565 Ikokwu GM Oseghale ID Omoregie I Ralph-Okhiria OH Ighile EF Emerging Trends in Antimicrobial Resistance and Novel Therapeutic Strategies International Journal of Pathogen Research 2023 12 10 26 10.9734/ijpr/2023/v12i3226 Mohr KI History of antibiotics research Curr Top Microbiol Immunol 2016 398 237 72 10.1007/82_2016_499 Iskandar K Murugaiyan J Halat DH Hage SE Chibabhai V Adukkadukkam S et al. Antibiotic Discovery and Resistance: The Chase and the Race Antibiotics (Basel) 2022 11 182 10.3390/antibiotics11020182 35203785 PMC8868473 Penesyan A Gillings M Paulsen IT Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities Molecules 2015 20 5286 98 10.3390/molecules20045286 25812150 PMC6272253 Mustajab M A Review on Antibiotics: History and Present IJARIIE 2021 7 379 83 Cunha BRd, Fonseca LP, Calado CRC. Antibiotic Discovery: Where Have We Come from, Where Do We Go? Antibiotics (Basel) 2019 8 45 10.3390/antibiotics8020045 31022923 PMC6627412 Goethem MWV Pierneef R Bezuidt OKI Peer YVD Cowan DA Makhalanyane TP A reservoir of ‘historical’ antibiotic resistance genes in remote pristine Antarctic soils Microbiome 2018 6 40 10.1186/s40168-018-0424-5 29471872 PMC5824556 Poulin-Laprade D Brouard J Gagnon N Turcotte A Langlois A Matte JJ et al. Resistance determinants and their genetic context in enterobacteria from a longitudinal study of pigs reared under various husbandry conditions Appl Environ Microbiol 2021 87 e02612 20 10.1128/AEM.02612-20 33514521 PMC8091121 Bian X Qu X Zhang J Nang SC Bergen PJ Zhou QT et al. Pharmacokinetics and pharmacodynamics of peptide antibiotics Adv Drug Deliv Rev 2022 183 114171 10.1016/j.addr.2022.114171 35189264 PMC10019944 Ullah H Ali S Classification of anti-bacterial agents and their functions Kumavath RN Antibacterial Agents IntechOpen; 2017. pp. 1–16. 10.5772/intechopen.68695 Xing H Liu X Lin J Sun M Huang J Li X et al. Trans-cinnamaldehyde inhibits Escherichia coli growth by regulating lipopolysaccharide accumulation Food Bioscience 2024 61 104559 10.1016/j.fbio.2024.104559 Rani S Singh H Ram C Efficacy and mechanism of carvacrol with octanoic acid against mastitis causing multi-drug-resistant pathogens Braz J Microbiol 2022 53 385 99 10.1007/s42770-021-00639-4 34784023 PMC8882502 Richardson LA Understanding and overcoming antibiotic resistance PLoS Biol 2017 15 e2003775 10.1371/journal.pbio.2003775 28832581 PMC5584968 Cheng Z Si X Tan H Zang Z Tian J Shu C et al. Cyanidin-3-O-glucoside and its phenolic metabolites ameliorate intestinal diseases via modulating intestinal mucosal immune system: potential mechanisms and therapeutic strategies Crit Rev Food Sci Nutr 2023 63 1629 47 10.1080/10408398.2021.1966381 34420433 Jiao F Bao Y Li M Zhang Y Zhang F Wang P et al. Unraveling the mechanism of ceftaroline-induced allosteric regulation in penicillin-binding protein 2a: insights for novel antibiotic development against methicillin-resistant Staphylococcus aureus Antimicrob Agents Chemother 2023 67 e0089523 10.1128/aac.00895-23 37971241 PMC10720500 Cada DJ Ingram K Baker DE Dalbavancin Hosp Pharm 2014 49 851 61 10.1310/hpj4909-851 25477617 PMC4252189 Brade KD Rybak JM Rybak MJ Oritavancin: A New Lipoglycopeptide Antibiotic in the Treatment of Gram-Positive Infections Infect Dis Ther 2016 5 1 15 10.1007/s40121-016-0103-4 26831328 PMC4811835 Katsnelson A Making Natural Products Supernatural ACS Cent Sci 2024 10 1125 8 10.1021/acscentsci.4c00695 38947207 PMC11212125 Ben T Wu K Ramkissoon A Aleksandrova E Purdy M See D et al. Discovery of a broad-spectrum, fluorinated macrobicyclic antibiotic through chemical synthesis ChemRxv® [Preprint]. 2024 [cited 2024 Oct 26]. Available from: https://chemrxiv.org/engage/chemrxiv/article-details/66f5783acec5d6c1424b65a5. 10.26434/chemrxiv-2024-llv6q Mitcheltree MJ Pisipati A Syroegin EA Silvestre KJ Klepacki D Mason JD et al. A synthetic antibiotic class overcoming bacterial multidrug resistance Nature 2021 599 507 12 10.1038/s41586-021-04045-6 34707295 PMC8549432 Ovung A Bhattacharyya J Sulfonamide drugs: structure, antibacterial property, toxicity, and biophysical interactions Biophys Rev 2021 13 259 72 10.1007/s12551-021-00795-9 33936318 PMC8046889 Rahal JJ Jr Simberkoff MS Bactericidal and bacteriostatic action of chloramphenicol against memingeal pathogens Antimicrob Agents Chemother 1979 16 13 8 10.1128/AAC.16.1.13 38742 PMC352780 Scarff JM Waidyarachchi SL Meyer CJ Lane DJ Chai W Lemmon MM et al. Aminomethyl spectinomycins: a novel antibacterial chemotype for biothreat pathogens J Antibiot (Tokyo) 2019 72 693 701 10.1038/s41429-019-0194-8 31164713 PMC6684479 Quinlivan EP McPartlin J Weir DG Scott J Mechanism of the antimicrobial drug trimethoprim revisited FASEB J 2000 14 2519 24 10.1096/fj.99-1037com 11099470 El-Gamal MI Brahim I Hisham N Aladdin R Mohammed H Bahaaeldin A Recent updates of carbapenem antibiotics Eur J Med Chem 2017 131 185 95 10.1016/j.ejmech.2017.03.022 28324783 Vaudaux P Waldvogel FA Gentamicin antibacterial activity in the presence of human polymorphonuclear leukocytes Antimicrob Agents Chemother 1979 16 743 9 10.1128/AAC.16.6.743 533256 PMC352946 Ezelarab HAA Abbas SH Hassan HA Abuo-Rahma GEA Recent updates of fluoroquinolones as antibacterial agents Arch Pharm (Weinheim) 2018 351 e1800141 10.1002/ardp.201800141 30048015 Nagarajan R Antibacterial activities and modes of action of vancomycin and related glycopeptides Antimicrob Agents Chemother 1991 35 605 9 10.1128/AAC.35.4.605 2069366 PMC245066 Rúben F Amador P Prudêncio C β-Lactams: chemical structure, mode of action and mechanisms of resistance Reviews and Research in Medical Microbiology 2013 24 7 17 10.1097/MRM.0b013e3283587727 Krause KM Serio AW Kane TR Connolly LE Aminoglycosides: An Overview Cold Spring Harb Perspect Med 2016 6 a027029 10.1101/cshperspect.a027029 27252397 PMC4888811 Lenz KD Klosterman KE Mukundan H Kubicek-Sutherland JZ Macrolides: From Toxins to Therapeutics Toxins (Basel) 2021 13 347 10.3390/toxins13050347 34065929 PMC8150546 Dinos GP The macrolide antibiotic renaissance Br J Pharmacol 2017 174 2967 83 10.1111/bph.13936 28664582 PMC5573421 Retsema J Fu W Macrolides: structures and microbial targets Int J Antimicrob Agents 2001 18 S3 10 10.1016/s0924-8579(01)00401-0 11574188 Mendes CddS, Antunes AMdS. Pipeline of Known Chemical Classes of Antibiotics Antibiotics (Basel) 2013 2 500 34 10.3390/antibiotics2040500 27029317 PMC4790266 Daghrir R Drogui P Tetracycline antibiotics in the environment: A review Environ Chem Lett 2013 11 209 27 10.1007/s10311-013-0404-8 Kocsis B Domokos J Szabo D Chemical structure and pharmacokinetics of novel quinolone agents represented by avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and nemonoxacin Ann Clin Microbiol Antimicrob 2016 15 34 10.1186/s12941-016-0150-4 27215369 PMC4878067 Pham TDM Ziora ZM Blaskovich MAT Quinolone antibiotics Medchemcomm 2019 10 1719 39 10.1039/c9md00120d 31803393 PMC6836748 Andriole VT The quinolones: past, present, and future Clin Infect Dis 2005 41 S113 9 10.1086/428051 15942877 Suay-García B Bueso-Bordils JI Antón-Fos G Pérez-Gracia MT Falcó A Alemán-López P Synthesis of Quinolones and Zwitterionic Quinolonate Derivatives with Broad-Spectrum Antibiotic Activity Pharmaceuticals 2022 15 818 10.3390/ph15070818 35890116 PMC9315932 Dai Y Toxicity Study of Sulfonamides Antibiotics Frontiers in Sustainable Development 2024 4 109 21 A. Greule and M. J. Cryle. The Glycopeptide Antibiotics Liu HW Begley TP Comprehensive Natural Products III Oxford Elsevier 2020 pp. 247–83. 10.1016/b978-0-12-409547-2.14691-8 Tian L Shi S Zhang X Han F Dong H Newest perspectives of glycopeptide antibiotics: biosynthetic cascades, novel derivatives, and new appealing antimicrobial applications World J Microbiol Biotechnol 2023 39 67 10.1007/s11274-022-03512-0 36593427 PMC9807434 Hansen MH Adamek M Iftime D Petras D Schuseil F Grond S et al. Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides Nat Commun 2023 14 7842 10.1038/s41467-023-43451-4 38030603 PMC10687080 Etebu, Ebimieowei, and Ibemologi Arikekpar. Antibiotics: Classification and mechanisms of action with emphasis on molecular perspectives Int J Appl Microbiol Biotechnol Res 2016 4 90 101 Bugg TDH Braddick D Dowson CG Roper DI Bacterial cell wall assembly: still an attractive antibacterial target Trends Biotechnol 2011 29 167 73 10.1016/j.tibtech.2010.12.006 21232809 Kohanski MA Dwyer DJ Collins JJ How antibiotics kill bacteria: from targets to networks Nat Rev Microbiol 2010 8 423 35 10.1038/nrmicro2333 20440275 PMC2896384 Newton BA Mechanisms of antibiotic action Annu Rev Microbiol 1965 19 209 40 10.1146/annurev.mi.19.100165.001233 5318438 Franklin TJ Cook JM The inhibition of nucleic acid synthesis by mycophenolic acid Biochem J 1969 113 515 24 10.1042/bj1130515 5807210 PMC1184694 Melander RJ Zurawski DV Melander C Narrow-Spectrum Antibacterial Agents Medchemcomm 2018 9 12 21 10.1039/C7MD00528H 29527285 PMC5839511 Stapleton PD Taylor PW Methicillin resistance in Staphylococcus aureus: mechanisms and modulation Sci Prog 2002 85 57 72 10.3184/003685002783238870 11969119 PMC2065735 Hudson AD Jamieson O Crapnell RD Rurack K Soares TCC Mecozzi F et al. Dual detection of nafcillin using a molecularly imprinted polymer-based platform coupled to thermal and fluorescence read-out Mater Adv 2021 2 5105 15 10.1039/d1ma00192b Bressler AM Williams T Culler EE Zhu W Lonsway D Patel JB et al. Correlation of penicillin Binding protein 2a detection with oxacillin resistance in Staphylococcus aureus and discovery of a novel penicillin binding protein 2a mutation J Clin Microbiol 2005 43 4541 4 10.1128/JCM.43.9.4541-4544.2005 16145104 PMC1234091 Grayson LM Kucers A Crowe S McCarthy J Mills J Mouton J Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs CRC Press; 2010. Ciriminna R Fidalgo A Meneguzzo F Presentato A Scurria A Nuzzo D et al. Pectin: A Long-Neglected Broad-Spectrum Antibacterial ChemMedChem 2020 15 2228 35 10.1002/cmdc.202000518 32857470 Belay WY Getachew M Tegegne BA Teffera ZH Dagne A Zeleke TK et al. Mechanism of antibacterial resistance, strategies and next-generation antimicrobials to contain antimicrobial resistance: A review Front Pharmacol 2024 15 1444781 10.3389/fphar.2024.1444781 39221153 PMC11362070 Luepke KH Suda KJ Boucher H Russo RL Bonney MW Hunt TD et al. Past, Present, and Future of Antibacterial Economics: Increasing Bacterial Resistance, Limited Antibiotic Pipeline, and Societal Implications Pharmacotherapy 2017 37 71 84 10.1002/phar.1868 27859453 Mancuso G Midiri A Gerace E Biondo C Bacterial Antibiotic Resistance: The Most Critical Pathogens Pathogens 2021 10 1310 10.3390/pathogens10101310 34684258 PMC8541462 Reygaert WC An overview of the antimicrobial resistance mechanisms of bacteria AIMS Microbiol 2018 4 482 501 10.3934/microbiol.2018.3.482 31294229 PMC6604941 Francine P Systems Biology: New Insight into Antibiotic Resistance Microorganisms 2022 10 2362 10.3390/microorganisms10122362 36557614 PMC9781975 Blaskovich MAT Hansford KA Butler MS Jia Z Mark AE Cooper MA Developments in Glycopeptide Antibiotics ACS Infect Dis 2018 4 715 35 10.1021/acsinfecdis.7b00258 29363950 PMC5952257 Sawa T Moriyama K Kinoshita M Current status of bacteriophage therapy for severe bacterial infections J Intensive Care 2024 12 44 10.1186/s40560-024-00759-7 39482746 PMC11529433 Li G Lai Z Shan A Advances of Antimicrobial Peptide-Based Biomaterials for the Treatment of Bacterial Infections Adv Sci (Weinh) 2023 10 e2206602 10.1002/advs.202206602 36722732 PMC10104676 Balcha FB Neja SA CRISPR-Cas9 mediated phage therapy as an alternative to antibiotics Animal Diseases 2023 3 4 10.1186/s44149-023-00065-z Barber M Drug combinations in antibacterial chemotherapy Proc R Soc Med 1965 58 990 5 4285323 PMC1898664 Lorente-Torres B Llano-Verdeja J Castañera P Ferrero HÁ Fernández-Martínez S Javadimarand F et al. Innovative Strategies in Drug Repurposing to Tackle Intracellular Bacterial Pathogens Antibiotics 2024 13 834 10.3390/antibiotics13090834 39335008 PMC11428606 Elebiju OF Oduselu GO Ogunnupebi TA Ajani OO Adebiyi E In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance Pharmaceuticals (Basel) 2024 17 543 10.3390/ph17050543 38794114 PMC11124240 Barragán-Cárdenas A Castellar-Almonacid D Vargas-Casanova Y Parra-Giraldo C Umaña-Pérez A López-Meza J et al. Enhanced breast cancer cell targeting: RGD integrin ligand potentiates RWQWRWQWR’s cytotoxicity and inhibits migration Explor Drug Sci 2024 2 369 88 10.37349/eds.2024.00052 Wankumbu SC Ji XM Xu M Decoding vascular aging: implications for atherosclerosis progression and clinical intervention Explor Drug Sci 2024 2 449 72 10.37349/eds.2024.00056 Chaubey GK Dilawari R Modanwal R Talukdar S Dhiman A Raje M Metformin in COVID-19: a magical role beyond the hyperglycemia Explor Drug Sci 2024 2 428 48 10.37349/eds.2024.00055 Safe S Natural products as anticancer agents and enhancing their efficacy by a mechanism-based precision approach Explor Drug Sci 2024 2 408 27 10.37349/eds.2024.00054 Ofir R Plants and fungi metabolites as novel autophagy inducers and senescence inhibitors Explor Drug Sci 2024 2 361 8 10.37349/eds.2024.00051 Iqbal K Milioudi A Wicha SG Pharmacokinetics and Pharmacodynamics of Tedizolid Clin Pharmacokinet 2022 61 489 503 10.1007/s40262-021-01099-7 35128625 PMC8975765 Lizza BD Betthauser KD Ritchie DJ Micek ST Kollef MH New Perspectives on Antimicrobial Agents: Ceftolozane-Tazobactam Antimicrob Agents Chemother 2021 65 e0231820 10.1128/AAC.02318-20 33875428 PMC8218675 Zhanel GG Schweizer F Karlowsky JA Oritavancin: mechanism of action Clin Infect Dis 2012 54 S214 9 10.1093/cid/cir920 22431851 Shirley M Ceftazidime-Avibactam: A Review in the Treatment of Serious Gram-Negative Bacterial Infections Drugs 2018 78 675 92 10.1007/s40265-018-0902-x 29671219 Dhillon S Meropenem/Vaborbactam: A Review in Complicated Urinary Tract Infections Drugs 2018 78 1259 1270 Erratum in: Drugs. 2018;78:1383. 10.1007/s40265-018-0966-7 30128699 PMC6132495 Stancil SL Mirzayev F Abdel-Rahman SM Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date Drug Des Devel Ther 2021 15 2815 30 10.2147/DDDT.S281639 34234413 PMC8253981 Veve MP Wagner JL Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic Pharmacotherapy 2018 38 935 46 10.1002/phar.2166 30019769 Bunick CG Keri J Tanaka SK Furey N Damiani G Johnson JL et al. Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation Antibiotics (Basel) 2021 10 439 10.3390/antibiotics10040439 33920812 PMC8071131 Clark JA Burgess DS Plazomicin: a new aminoglycoside in the fight against antimicrobial resistance Ther Adv Infect Dis 2020 7 2049936120952604 10.1177/2049936120952604 32953108 PMC7475792 Wang S Zhao K Chen Z Liu D Tang S Sun C et al. Halicin: A New Horizon in Antibacterial Therapy against Veterinary Pathogens Antibiotics (Basel) 2024 13 492 10.3390/antibiotics13060492 38927159 PMC11200678 Mohammadi MR Zoliflodacin: A hope to treat antibiotic-resistant Neisseria gonorrhoeae Journal of Medical Bacteriology 2023 11 27 35 10.18502/jmb.v11i1-2.14372 Yang Q Xu Y Jia P Zhu Y Zhang J Zhang G et al. In vitro activity of sulbactam/durlobactam against clinical isolates of Acinetobacter baumannii collected in China J Antimicrob Chemother 2020 75 1833 9 10.1093/jac/dkaa119 32306049 Logan A Wolfe A Williamson JC Antifungal Resistance and the Role of New Therapeutic Agents Curr Infect Dis Rep 2022 24 105 16 10.1007/s11908-022-00782-5 35812838 PMC9255453