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Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring...
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Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (20 February 2026) | Viewed by 20301

Special Issue Editors

Dr. Rok Frlan

E-Mail Website
Guest Editor
The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Interests: antibiotics; drug design; Mur ligases; cell wall; medicinal chemistry; peptidoglycan; computer-aided drug design; machine learning
Special Issues, Collections and Topics in MDPI journals
Dr. Martina Hrast

E-Mail Website
Guest Editor
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Interests: design and synthesis of low molecular inhibitors; inhibitors of bacterial cell wall; Mur enzymes; penicillin binding proteins; InhA inhibitors; DNA girase inhibitors; FtsZ inhibitors; enzymatic and antibacterial evaluation of compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The inappropriate use of antibacterial agents has promoted the emergence of resistant strains of bacteria and poses a significant threat to public health. The pervasive problem of antimicrobial resistance (AMR) is exacerbating healthcare crises worldwide, leading to increased mortality rates and rising healthcare costs. According to the World Health Organization (WHO), antibiotic resistance could cause up to 10 million deaths a year worldwide by 2050. Research into new antibiotics is therefore urgently needed.

This Special Issue aims to present a broad spectrum of research in the field of medicinal chemistry of antibacterial compounds and we welcome manuscripts that address both traditional and computational drug design strategies, from target identification to the application of machine learning and the screening of diverse chemical libraries in the discovery processes. In terms of publication priorities, modern methods, including virulence factor inhibitors, nanoparticles, antimicrobial peptides, phage therapy, and antisense oligonucleotides, are at the forefront. Papers dealing with the design and synthesis of new classes of antibacterial agents that introduce novel mechanisms of action, as well as studies focusing on the chemical synthesis and optimization of existing antibacterial agents, whether semi-synthetic or fully synthetic, are also welcome.

We are keen to publish ground-breaking research on the design and development of novel antibacterial agents for human and veterinary medicine. Authors are encouraged to submit original papers or reviews covering all aspects of this important topic.

Dr. Rok Frlan
Dr. Martina Hrast
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design
  • synthesis of novel antibacterial agents
  • computational chemistry
  • repurposing of drugs
  • novel antibacterial mechanisms

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Related Special Issue

Published Papers (7 papers)

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Research

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29 pages, 6560 KB  
Article
In Silico Druggability Assessment of Escherichia coli FtsQ Reveals Tractable PPI Interfaces in the Divisome
by Rok Frlan
Antibiotics 2026, 15(5), 430; https://doi.org/10.3390/antibiotics15050430 - 24 Apr 2026
Viewed by 212
Abstract
Background/Objectives: Due to the widespread problem of antimicrobial resistance (AMR), there is an urgent need to identify new antibacterial targets that act through mechanisms distinct from those of existing antibiotics. One of these targets is the essential cell division protein FtsQ, which [...] Read more.
Background/Objectives: Due to the widespread problem of antimicrobial resistance (AMR), there is an urgent need to identify new antibacterial targets that act through mechanisms distinct from those of existing antibiotics. One of these targets is the essential cell division protein FtsQ, which is a central hub of the Gram-negative divisome, but the druggability of its extensive protein–protein interaction (PPI) interfaces remains poorly defined. Here, we present a comprehensive structure-based in silico characterization of Escherichia coli FtsQ aimed at identifying and prioritizing druggable regions for PPI modulation. Methods: We analyzed E. coli FtsQ in both apo and complexed states (FtsQB, FtsQL, and FtsQBL) using a combination of pocket-mapping tools (FTMap and SiteMap), evolutionary conservation analysis (ConSurf), and structure property assessment (BLAST, ProBiS) to map and evaluate potential binding pockets of FtsQ protein. Results: Eight potential binding sites were predicted across the β and POTRA domains of FtsQ. One previously unreported site within the POTRA domain was prioritized as a candidate site, characterized by favorable druggability scores, strong evolutionary conservation, and a putative role in the FtsQ–FtsW/FtsN/FtsI interaction network. In contrast, two highly conserved sites at the FtsQ–FtsB/FtsL interaction interface were structurally flat, indicating limited suitability for classical small-molecule binding and greater compatibility with alternative modalities such as macrocycles or peptidomimetics. Conclusions: Although FtsQ lacks deep canonical binding pockets, this study proposes several conserved and potentially tractable regions as candidate sites, supporting its potential as a non-classical but promising antibacterial target for disrupting bacterial cytokinesis. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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25 pages, 7494 KB  
Article
Escaping the ESKAPE Antimicrobial Resistant Cycle with EVQ-218
by Ali Sakawa Sharif, Kayla C. Maas, Isabella Fratangelo, Kenneth J. Woolley, David B. Nilson and William H. Niedermeyer
Antibiotics 2026, 15(2), 224; https://doi.org/10.3390/antibiotics15020224 - 18 Feb 2026
Viewed by 1636
Abstract
Background/Objectives: Antimicrobial resistance (AMR) continues to expand under sustained exposure to conventional antibiotics, contributing to the emergence of multidrug- and pan-resistant bacterial pathogens. There remains a critical need for antimicrobial agents that maintain activity during prolonged selective pressure while minimizing the potential for [...] Read more.
Background/Objectives: Antimicrobial resistance (AMR) continues to expand under sustained exposure to conventional antibiotics, contributing to the emergence of multidrug- and pan-resistant bacterial pathogens. There remains a critical need for antimicrobial agents that maintain activity during prolonged selective pressure while minimizing the potential for resistance development. This study aimed to evaluate EVQ-218, a non-ionic silver-based antimicrobial, against World Health Organization-designated ESKAPE pathogens. Methods: EVQ-218 was assessed using extended serial passage experiments performed under both sub- and supra-minimum inhibitory concentration (MIC) conditions. Comparative resistance selection experiments were conducted in parallel using tobramycin and ciprofloxacin, and susceptibility was evaluated through MIC determination and phenotypic analysis. Results: Across extended serial passage experiments, EVQ-218 did not exhibit measurable increases in MIC or phenotypic indicators of adaptive resistance. In contrast, parallel exposure to tobramycin and ciprofloxacin resulted in rapid and sustained MIC elevation. Notably, isolates that acquired resistance to either comparator antibiotic retained susceptibility to EVQ-218, indicating a lack of cross-resistance. Mechanistic analyses were consistent with a non-lytic, intracellular mode of antibacterial activity involving disruption of sulfur-associated biomolecular processes, suggestive of a multi-site mechanism distinct from classical antibiotics. Conclusions: These findings support EVQ-218 as a promising broad-spectrum antimicrobial candidate with resistance-resilient activity and warrant further investigation of its potential role in addressing unmet needs in AMR therapeutics. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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14 pages, 942 KB  
Article
Dietary Pistachio Skin Effects on Antibiotic-Free Lamb: Virulence Traits, Antimicrobial Resistance, and Clonal Relatedness in Commensal Escherichia coli Strains
by Nunziatina Russo, Georgiana Bosco, Lisa Solieri, Maria Ronsivalle, Alessandra Pino, Amanda Vaccalluzzo, Cinzia Caggia and Cinzia Lucia Randazzo
Antibiotics 2026, 15(2), 160; https://doi.org/10.3390/antibiotics15020160 - 3 Feb 2026
Viewed by 723
Abstract
Background/Objectives: In food-producing animal (FPA) environments, healthy animals can act as reservoirs of potentially pathogenic Escherichia coli, which can be transmitted through the food chain to humans. This study aimed to evaluate cloacal E. coli in healthy Sicilian lambs subjected to [...] Read more.
Background/Objectives: In food-producing animal (FPA) environments, healthy animals can act as reservoirs of potentially pathogenic Escherichia coli, which can be transmitted through the food chain to humans. This study aimed to evaluate cloacal E. coli in healthy Sicilian lambs subjected to an experimental feeding regimen by assessing bacterial levels, antimicrobial resistance, virulence traits, and the clonal relationships, as well as the impact of a pistachio skin as an agro-industrial by-product supplement during a 58-day feeding trial. Methods: A total of 295 E. coli isolates from the control (CTRL) and treatment (Treated) groups at initial time (T0) and final time (T1) were phenotypically and genotypically characterized using Kirby–Bauer antimicrobial testing, multiplex PCR for virulence genes, and PFGE for clonal analysis. Results: The feeding regimen did not significantly influence the prevalence, abundance, or virulence of the E. coli isolates. Shiga toxin-producing E. coli (STEC) were the most common pathotype, mainly carrying the stx1 gene, while the Enteroinvasive (EIEC) type was detected only sporadically. Enteropathogenic E. coli (EPEC) predominated at T0, while enteroaggregative E. coli (EAEC) at T1, and enterotoxigenic E. coli (ETEC), initially prevalent in Treated samples, disappeared by T1. Antimicrobial resistance profiles varied among isolates, with the highest resistance observed in the CTRL group. However, both groups exhibited high resistance to streptomycin, and 9% of CTRL isolates were multidrug resistant. A notable reduction in overall resistance rates, especially in the Treated group, was observed, indicating a dietary effect on the E. coli resistome. PFGE genotyping showed high genetic diversity, with resistance traits more frequently detected than virulence factors. Conclusions: This study highlights that healthy lambs serve as reservoirs for potentially human-pathogenic E. coli and suggests that dietary regimes could effectively reduce antibiotic resistance. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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11 pages, 663 KB  
Article
In Vitro Activity of Zoliflodacin Against Neisseria gonorrhoeae Isolates from Shanghai, China (2020–2023)
by Linxin Yao, Tingli Tian, Xinying Lu, Danyang Zou, Zhuojun Tang, Xin Feng, Tong Zheng, Zhen Ning, Yi Lin, Meiping Ye, Jianping Jiang and Pingyu Zhou
Antibiotics 2026, 15(1), 61; https://doi.org/10.3390/antibiotics15010061 - 5 Jan 2026
Cited by 3 | Viewed by 1375
Abstract
Background/Objectives: The escalating threat of drug-resistant Neisseria gonorrhoeae underscores the urgent need for novel therapeutic agents. Zoliflodacin, a first-in-class spiropyrimidinetrione antibiotic that targets bacterial DNA gyrase and topoisomerase IV, represents a promising candidate for gonorrhea treatment. Methods: From 2020 to 2023, a total [...] Read more.
Background/Objectives: The escalating threat of drug-resistant Neisseria gonorrhoeae underscores the urgent need for novel therapeutic agents. Zoliflodacin, a first-in-class spiropyrimidinetrione antibiotic that targets bacterial DNA gyrase and topoisomerase IV, represents a promising candidate for gonorrhea treatment. Methods: From 2020 to 2023, a total of 876 urogenital N. gonorrhoeae isolates were collected from 35 hospitals across Shanghai, China. In vitro susceptibilities to zoliflodacin and six conventional antibiotics (penicillin, tetracycline, ciprofloxacin, azithromycin, ceftriaxone, and spectinomycin) were determined using the agar dilution method. Whole-genome sequencing was conducted to identify sequence types (STs) and amino-acid substitutions in GyrA, GyrB, ParC, ParE, and MtrR. Results: Zoliflodacin exhibited potent in vitro activity, with minimum inhibitory concentrations (MICs) ranging from ≤0.004 to 0.25 mg/L (MIC50 = 0.06 mg/L; MIC90 = 0.125 mg/L), all below the breakpoint (0.5 mg/L). Notably, zoliflodacin maintained high activity against isolates resistant to ceftriaxone, azithromycin, ciprofloxacin, penicillin, and tetracycline. Although all isolates were susceptible to zoliflodacin, elevated MIC values were observed in ST7363 and ST8123 compared with other clones. Genomic analysis identified no substitutions associated with increased zoliflodacin MICs, and most GyrB sequences, the key gene associated with zoliflodacin resistance, remained intact. Conclusions: These findings demonstrate that zoliflodacin possesses robust activity against circulating multidrug-resistant N. gonorrhoeae lineages in Shanghai and support its potential clinical use for the treatment of gonorrhea. Continued genomic and phenotypic surveillance is warranted to preserve the long-term efficacy of this novel agent. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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15 pages, 7966 KB  
Article
Anticandidal Properties of Launaea sarmentosa among the Salt Marsh Plants Collected from Palk Bay and the Gulf of Mannar Coast, Southeastern India
by Smriti Das, Karuppannagounder Rajan Priyanka, Kolandhasamy Prabhu, Ramachandran Vinayagam, Rajendran Rajaram and Sang Gu Kang
Antibiotics 2024, 13(8), 748; https://doi.org/10.3390/antibiotics13080748 - 9 Aug 2024
Cited by 3 | Viewed by 2414
Abstract
Tidal wetlands, commonly known as salt marshes, are highly productive ecosystems in temperate regions worldwide. These environments constitute a unique flora composed primarily of salt-tolerant herbs, grasses, and shrubs. This study investigated the therapeutic properties of ten salt marsh plants collected mainly from [...] Read more.
Tidal wetlands, commonly known as salt marshes, are highly productive ecosystems in temperate regions worldwide. These environments constitute a unique flora composed primarily of salt-tolerant herbs, grasses, and shrubs. This study investigated the therapeutic properties of ten salt marsh plants collected mainly from Palk Bay and Mannar Gulf against Candida disease. This study examined the changes in natural plant products associated with their anti-Candida growth activity during two distinct seasonal changes—monsoon and summer. The potential of the salt marshes to inhibit the growth of five different Candida strains was assessed using four solvents. In phytochemical analysis, the extracts obtained from a Launaea sarmentosa exhibited the highest results compared to the other plant extracts. Fourier transform infrared spectroscopy revealed 12 peaks with alkane, aldehyde, amine, aromatic ester, phenol, secondary alcohol, and 1,2,3,4-tetrasubstituted. Gas-chromatography–mass spectrometry detected 30 compounds. Cyclotetracosane, lupeol, β-amyrin, and 12-oleanen-3-yl acetate showed the highest peak range. In particular, plant samples collected during the monsoon season were more effective in preventing Canda growth than the summer plant samples. In the monsoon season, the salt marsh plant extracted with ethyl acetate showed a high anti-Candida growth activity, while in the summer, the acetone extract exhibited a higher anti-Candida growth activity than the other solvents. The hexane extract of L. sarmentosa showed the highest inhibition zone against all Candidal strains. Furthermore, compounds, such as β-amyrin, lupeol, and oxirane, from the hexane extract of L. sarmentosa play a vital role in anti-Candida activity. This paper reports the potential of tidal marsh plant extracts for developing new antifungal agents for Candida infections. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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Review

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26 pages, 2293 KB  
Review
Combatting Pseudomonas aeruginosa with β-Lactam Antibiotics: A Revived Weapon?
by Dylan W. Zhao and Christopher T. Lohans
Antibiotics 2025, 14(5), 526; https://doi.org/10.3390/antibiotics14050526 - 20 May 2025
Cited by 4 | Viewed by 7780
Abstract
Pseudomonas aeruginosa is a significant threat to public health as an aggressive, opportunistic pathogen. The use of β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems remains a front-line treatment against P. aeruginosa. However, the widespread use of β-lactams has led to [...] Read more.
Pseudomonas aeruginosa is a significant threat to public health as an aggressive, opportunistic pathogen. The use of β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems remains a front-line treatment against P. aeruginosa. However, the widespread use of β-lactams has led to the emergence of β-lactam-resistant isolates that significantly increase the economic burden and risk of mortality in patients. With the declining productivity of the antibiotic discovery pipeline, research has investigated synergistic agents to revive the use of β-lactam antibiotics against β-lactam-resistant P. aeruginosa. In this review, we summarize the mechanism of β-lactam antibiotics and provide an overview of major mechanisms associated with β-lactam resistance in P. aeruginosa. We then describe the background and use of three promising classes of agents that have shown extensive beneficial effects with β-lactam antibiotics against P. aeruginosa, namely β-lactamase inhibitors, bacteriophages, and antimicrobial peptides. The current understanding of the mechanisms of these synergistic agents is discussed. Lastly, we provide an overview of the current barriers impeding antibiotic development, and offer a glimpse into recent advances of artificial intelligence-based discovery that may serve as a new foundation for antimicrobial discovery and treatment. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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46 pages, 1890 KB  
Review
Antimicrobial Metabolites of Caucasian Medicinal Plants as Alternatives to Antibiotics
by Marta Fik-Jaskółka, Valentina Mittova, Catherine Motsonelidze, Malkhaz Vakhania, Caterina Vicidomini and Giovanni N. Roviello
Antibiotics 2024, 13(6), 487; https://doi.org/10.3390/antibiotics13060487 - 24 May 2024
Cited by 27 | Viewed by 4982
Abstract
This review explores the potential of antimicrobial metabolites derived from Caucasian medicinal plants as alternatives to conventional antibiotics. With the rise of antibiotic resistance posing a global health threat, there is a pressing need to investigate alternative sources of antimicrobial agents. Caucasian medicinal [...] Read more.
This review explores the potential of antimicrobial metabolites derived from Caucasian medicinal plants as alternatives to conventional antibiotics. With the rise of antibiotic resistance posing a global health threat, there is a pressing need to investigate alternative sources of antimicrobial agents. Caucasian medicinal plants have traditionally been used for their therapeutic properties, and recent research has highlighted their potential as sources of antimicrobial compounds. Representatives of 15 families of Caucasian medicinal plant extracts (24 species) have been explored for their efficacy against these pathogens. The effect of these plants on Gram-positive and Gram-negative bacteria and fungi is discussed in this paper. By harnessing the bioactive metabolites present in these plants, this study aims to contribute to the development of new antimicrobial treatments that can effectively combat bacterial infections while minimizing the risk of resistance emergence. Herein we discuss the following classes of bioactive compounds exhibiting antimicrobial activity: phenolic compounds, flavonoids, tannins, terpenes, saponins, alkaloids, and sulfur-containing compounds of Allium species. The review discusses the pharmacological properties of selected Caucasian medicinal plants, the extraction and characterization of these antimicrobial metabolites, the mechanisms of action of antibacterial and antifungal plant compounds, and their potential applications in clinical settings. Additionally, challenges and future directions in the research of antimicrobial metabolites from Caucasian medicinal plants are addressed. Full article
(This article belongs to the Special Issue Innovations in Antibacterial Agents: Combating Resistance, Improving Efficacy and Exploring New Mechanisms)
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