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Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials

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A Special Issue of Pathogens (ISSN 2076-0817) belonging to the section "Vaccines and Therapeutic Developments".

Deadline for manuscript submissions: 15 December 2026 | Viewed by 16911

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Dr. Elizabete de Souza Cândido

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S-Inova Biotech, Programa de Pós Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande 79117900, Brazil
Interests: antimicrobial peptides; microbial resistance; plant antimicrobial peptides; proteomics; peptidomics
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Special Issue Information

Dear Colleagues,

The emergence and spread of multidrug-resistant (MDR) bacteria represents one of the most pressing global health challenges of our time, threatening to undermine modern medicine and public health. This Special Issue focuses on the complex interplay between bacterial resistance mechanisms and the development of novel antibacterial strategies. We invite high-quality, original research articles and reviews that address the molecular basis of resistance, including horizontal gene transfer, efflux pumps, and target-site modifications, as well as innovative approaches to combat MDR pathogens.

We particularly welcome studies that explore the following topics: (i) the discovery and characterization of new antimicrobial compounds, including natural products, synthetic molecules, and repurposed drugs; (ii) alternative therapeutic strategies, such as phage therapy, antimicrobial peptides, and CRISPR-based technologies; (iii) the role of biofilms and persister cells in chronic infections; and (iv) the impact of environmental and clinical factors on the evolution of resistance. Submissions may cover a broad range of bacterial pathogens; emphasis will be placed on ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) and other clinically relevant MDR strains.

By bringing together cutting-edge research on resistance mechanisms and drug development, this Special Issue aims to contribute to the global effort to combat antimicrobial resistance (AMR) and safeguard the future of infectious disease treatment.

Dr. Elizabete de Souza Cândido
Guest Editor

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens 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 2400 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

antimicrobial resistance (AMR)
multidrug-resistant (MDR) bacteria
novel antibiotics
resistance mechanisms
alternative therapies
ESKAPE pathogens

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Published Papers (8 papers)

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Research

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16 pages, 2188 KB

Open AccessEditor’s ChoiceArticle

Effect of trans-Cinnamaldehyde on Adhesion and Other Virulence Factors of Methicillin-Resistant Staphylococcus aureus

by Barbara Kot, Kamila Wierzchowska, Agata Grużewska, Elżbieta Anna Trafny, Małgorzata Stępińska and Małgorzata Witeska

Pathogens 2026, 15(3), 271; https://doi.org/10.3390/pathogens15030271 - 3 Mar 2026

Cited by 1 | Viewed by 1347

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) produces virulence factors and causes hard-to-treat infections. This study aimed to evaluate the effect of trans-cinnamaldehyde (TC) on the selected virulence factors of MRSA: adhesion to host plasma and extracellular matrix proteins, protease, DNase and esterase production, and hemolytic activity. Our results showed that TC at ½ MBIC (Minimum Biofilm Inhibition Concentration) of 240 µg/mL or 60 µg/mL, depending on the isolate, significantly reduced MRSA adhesion. Inhibition varied between isolates, ranging from 26.1% to 41.3% (fibrinogen), 18.2% to 34.9% (elastin), 26.5% to 32.4% (laminin), and 17.1% to 30.5% (collagen). TC at ½ MIC (Minimum Inhibitory Concentration) of 30 µg/mL also significantly inhibited MRSA enzyme production, and reduced hemolytic activity (by 80.0–83.1%, depending on the isolate). TC may be an alternative to antibiotics for combating infections caused by S. aureus, as it not only reduces bacterial survival in the host but also reduces S. aureus virulence at subinhibitory concentrations. TC at higher concentrations exhibits cytotoxicity in human fibroblasts, limiting its topical use. Therefore, to exploit TC’s antibacterial potential, it is necessary to identify substances that act synergistically with it, enabling reduced effective doses. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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16 pages, 276 KB

Open AccessArticle

Antibiotic Outcomes of Enterococcal Urinary Tract Infections: A Retrospective Analysis from Saudi Arabia and Oman

by Abrar K. Thabit, Juhaina S. Al-Maqbali, Khaled F. Alharthi, Salem M. Baotab, Abdullah M. Bankhar, Rayyan M. Wali, Mohammed O. Alzahrani, Asiya K. Alharthi, Taqwa M. Alhamsaidi, Ibrahim Al Busaidi, Ahmad J. Mahrous and Jimmy Jose

Pathogens 2026, 15(3), 250; https://doi.org/10.3390/pathogens15030250 - 26 Feb 2026

Viewed by 2726

Abstract

Background: Enterococcus species are involved in urinary tract infections (UTIs), and they are known to be intrinsically resistant to certain antibiotics. We aimed to investigate the clinical characteristics and treatment outcomes of enterococcal UTIs in three hospitals in Saudi Arabia and Oman. Methods: A retrospective cohort study was conducted on adults with clinically and microbiologically confirmed enterococcal UTI based on urinary symptoms and a urine culture of ≥100,000 CFU/mL, who received an antibiotic active against the pathogen. The primary endpoint was clinical cure. Secondary endpoints included microbiological cure, length of stay (LOS), in-hospital mortality, and recurrence. Results: E. faecalis and E. faecium were isolated from 188 (67.1%) and 92 (32.9%), respectively, of 280 included patients. Ampicillin/amoxicillin (25%) and vancomycin (22.1%) were the most-used antibiotics. Compared with E. faecium, E. faecalis was associated with higher clinical cure rates (75% vs. 57.6%; p = 0.003), lower in-hospital mortality (15.7% vs. 38.5%; p < 0.0001), and shorter LOS (12.5 vs. 25 days; p < 0.0001). No difference in recurrence was observed. Ciprofloxacin was associated with high odds of clinical cure (OR, 4.28; 95% CI, 1.18–15.56). Conversely, the recent cancer chemotherapy and growth of Enterococcus at another site were associated with lower odds of clinical cure. Urinary catheter removal was associated with lower recurrence odds (OR, 0.48; 95% CI, 0.24–0.98). Conclusions: This study highlights the clinical challenges posed by enterococcal UTIs, particularly by E. faecium. Ciprofloxacin remains an effective option, particularly against E. faecalis. Patients with advanced age, critical illness, complicated infections, and liver disease, as well as patients on hemodialysis, require close monitoring to improve outcomes. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

13 pages, 370 KB

Open AccessArticle

Benzalkonium Chloride Tolerance Among Listeria innocua from Food and Food Processing Environments in Poland

by Anna Zawiasa, Aleksandra Andrzejewska, Patryk Mikołajczak and Agnieszka Olejnik-Schmidt

Pathogens 2026, 15(1), 76; https://doi.org/10.3390/pathogens15010076 - 10 Jan 2026

Viewed by 844

Abstract

Benzalkonium chloride (BC) is widely used as a disinfectant in the food industry; however, increasing reports of Listeria innocua isolates exhibiting tolerance to this compound highlight the need to better understand their adaptive mechanisms. This study aimed to evaluate BC tolerance in 51 L. innocua isolates originating from raw and processed meat products (n = 32) and meat-processing environments in Poland (n = 19). Phenotypic tolerance was assessed using the agar diffusion method on two media: Brain Heart Infusion (BHI) agar and Mueller–Hinton (M-H) agar supplemented with 1.2% sheep blood, across BC concentrations of 0, 5, 10, 15, 20, 25, 30, 35, 40, and 45 µg/mL, allowing the determination of minimum inhibitory concentrations (MICs). Genotypic analysis of tolerance determinants (brcABC, ermC, qacE, qacF, qacG, qacH, and qacJ) was performed by PCR. On BHI agar, MIC values ranged from 15 to 30 µg/mL, with 15 µg/mL most frequently observed, whereas on blood-supplemented M-H agar, MICs were lower (5–20 µg/mL), most commonly 10 µg/mL. Among tolerance-associated genes, qacH was the most prevalent (29% of isolates), followed by brcABC (4%) and ermC (2%), while the remaining genes were absent. These findings suggest that food products may serve as a reservoir for L. innocua isolates harboring tolerance to BC and contribute to a deeper understanding of how this species adapts to quaternary ammonium compounds. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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19 pages, 961 KB

Open AccessEditor’s ChoiceArticle

Prevalence of ESBL-Producing Escherichia coli on Neck Skin in Slaughtered Broilers Raised on Conventional, Antibiotic-Free, and Organic Farms

by Giulia Dilio, Francesca Blasi, Silvia Tofani, Elisa Albini, Serenella Orsini, Marcella Ciullo, Francesca Romana Massacci, Michele Pesciaroli, Giovanni Pezzotti and Chiara Francesca Magistrali

Pathogens 2025, 14(12), 1265; https://doi.org/10.3390/pathogens14121265 - 10 Dec 2025

Cited by 3 | Viewed by 1547

Abstract

Antimicrobial resistance (AMR) among commensal Escherichia coli from poultry is a growing concern for food safety and public health. This study investigated AMR patterns in E. coli isolated from broiler neck skin at slaughter, comparing organic, antibiotic-free (ATB-free), and conventional production systems. A total of 375 samples were collected from two Italian slaughterhouses and tested by broth microdilution following EU protocols. E. coli was recovered from 358 samples, and 37.9% were presumptively positive for ESBL/AmpC-producing strains. Conventional broilers showed the highest resistance to ampicillin (73.8%), sulfonamides (72.5%), and fluoroquinolones (nalidixic acid, 62.5%; ciprofloxacin, 67.5%), while organic and ATB-free systems showed significantly lower levels. Intermediate resistance occurred for trimethoprim (21.4–47.9%) and tetracycline (36–54%), and low prevalence (<10%) was found for gentamicin, tigecycline, and third-generation cephalosporins. No relevant resistance was detected to colistin or carbapenems (≤1.2%). Total E. coli counts did not differ among systems, suggesting differences in resistant strain proportions rather than bacterial load. ATB-free flocks processed after conventional batches displayed higher resistance, indicating possible cross-contamination during slaughter. These results highlight the influence of farming practices and slaughterhouse hygiene on AMR dissemination, underscoring the need for integrated farm-to-slaughter control strategies. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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12 pages, 635 KB

Open AccessArticle

Antimicrobial Resistance Transmission of Multidrug-Resistant Bacteria in Hydroponic Farming Components

by Qian Zhang, Ye Htut Zwe, Daisuke Sano and Dan Li

Pathogens 2025, 14(11), 1134; https://doi.org/10.3390/pathogens14111134 - 8 Nov 2025

Cited by 2 | Viewed by 1616

Abstract

Hydroponic farming offers sustainability benefits, but its microbial safety remains a concern, particularly regarding antimicrobial resistance (AMR) transmission. This study evaluated the potential for conjugative plasmid transfer of multidrug-resistant bacteria in hydroponic systems, using Salmonella Saintpaul B23 as a donor and various Escherichia coli strains and a self-isolated Salmonella strain from a hydroponic system as recipients. The tested bacteria are human enteric bacteria and may have a chance of being introduced into hydroponic systems. The transconjugation assay was conducted in hydroponic solutions and on different hydroponic components. Results revealed that hydroponic solutions and plant substrates could support significant transconjugation (>4 log CFU transconjugants detected in per mL hydroponic solution and >4 log CFU transconjugants detected in per g plant substrates), while facility surfaces showed minimal transfer (<1 log CFU transconjugants detected on per cm² surface). UV irradiation reduced plasmid transfer rates significantly (p < 0.05), suggesting its potential as a mitigation strategy, though proper implementation is critical. Antibiotic residues at sub-minimum inhibitory concentrations exhibited varying effects on AMR propagation, with gentamicin and chloramphenicol unexpectedly reducing transconjugants. These findings highlight the complex dynamics of AMR transmission in hydroponics and underscore the importance of monitoring, UV application, and cautious use of recycled waste to ensure microbial safety and mitigate AMR risks in agricultural production. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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25 pages, 877 KB

Open AccessEditor’s ChoiceReview

Treating Extensively Drug-Resistant Acinetobacter baumannii: Considerations for Host Characteristics and Type of Infections

by Anastasia Geladari, Dimitrios Kouroupis, Kyriaki Vafeidou, Vasileios Liakos, Maria Magoudi, Anastasia-Izampella Papathanasiou, Elias Iosifidis, Emmanuel Roilides, Charalampos Antachopoulos and Athina Pyrpasopoulou

Pathogens 2026, 15(1), 81; https://doi.org/10.3390/pathogens15010081 - 12 Jan 2026

Cited by 1 | Viewed by 4133

Abstract

Acinetobacter baumannii has been characterized by CDC, WHO and most National Healthcare Systems worldwide as a critical nosocomial pathogen, and classified as an ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) pathogen. Mortality of invasive infections due to A. baumannii exceeds 40%. To highlight its impact on public health, ECDC has organized a special project on national lab co-ordination to accurately detect and report carbapenem-resistant strains, to identify epidemiological factors for infection (or colonization) with carbapenem-resistant A. baumanii at clonal and sub-genomic level. This review aims to describe the history, epidemiology, and evolution of resistance of A. baumannii, and stress the caveats associated with the management of systemic infections. Available active antimicrobials and drugs in the pipeline are listed, and available clinical evidence on their pharmacokinetics and efficacy in various types of infections are described. Clinician’s choice of treatment (drug, and monotherapy vs. combination treatment) depends on the patients’ profile, site of infection and antimicrobial resistance profile. Emphasis is laid on specific patient subpopulations, whose management is discussed. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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41 pages, 2975 KB

Open AccessReview

Taming Superbugs: Current Progress and Challenges in Combating ESKAPE Pathogens

by Helal F. Hetta, Fatma R. Khalaf, Ahmed A. Kotb, Marah N. Alatawi, Abdullah S. Albalawi, Ahmad A. Alharbi, Maryam K. Aljohani, Shumukh Saad Aljohani, Majd S. Alatawi, Noura H. Abd Ellah, Basem Battah, Matthew G. Donadu and Vittorio Mazzarello

Pathogens 2026, 15(1), 28; https://doi.org/10.3390/pathogens15010028 - 24 Dec 2025

Cited by 8 | Viewed by 3124

Abstract

The global incidence of multidrug-resistant (MDR) ESKAPE pathogens—comprising Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—has surged alarmingly in recent years, posing a significant challenge to healthcare systems worldwide. These organisms are notorious for their capacity to evade the effects of multiple classes of antibiotics, leading to treatment failures, increased morbidity and mortality, and escalating healthcare costs, all of which have placed unprecedented strain on existing infection control measures. This review encapsulates the progress in target-driven vaccine research, including the genomic discovery of highly conserved surface antigens, iron acquisition systems, biofilm- and quorum-sensing-related proteins, and computationally predicted epitopes, which are considered the most attractive targets for broad-spectrum vaccination. Novel vaccine platforms, such as outer membrane vesicles (OMVs), mRNA technologies, and multi-epitope constructs, will rapidly drive the translation of these targets into next-generation vaccine formulations. Nevertheless, challenges such as antigenic variation and immune evasion, as well as the need for a robust mucosal and cross-protective immune response, persist. The sustainability in interdisciplinary investigations are required, along with adjunctive measures and investment in the development of advanced discovery and delivery systems, to achieve the ultimate goal of successful vaccines against MDR ESKAPE infections and to mitigate the worldwide burden of antimicrobial resistance. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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Other

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13 pages, 566 KB

Open AccessCase Report

Prosthetic Valve Endocarditis by Acinetobacter baumannii: Case Report and Systematic Descriptive Review

by Annabella Salvati, Loredana Alessio, Gloria Trombaccia, Giovanni Cimmino, Marisa De Feo, Fausto Ferraro, Stefania De Pascalis and Nicola Coppola

Pathogens 2026, 15(6), 581; https://doi.org/10.3390/pathogens15060581 - 28 May 2026

Cited by 1 | Viewed by 728

Abstract

A 61-year-old woman developed prosthetic valve infective endocarditis after osteomyelitis caused by extensively drug-resistant (XDR) Acinetobacter baumannii. Moreover, a systematic descriptive review of published case reports was performed to describe the main features, treatment, and outcomes of this condition. Methods: Apart from the description of our case, a PubMed and Embase literature review was conducted up to January 2026 using the terms “A. baumannii” AND (“infective endocarditis” OR “endocarditis” OR “valvular infection”). We included clinical cases of IE caused by A. baumannii published as full-text articles in English. Results: After orthopedic osteosynthesis surgery following a femur fracture, our patient developed osteomyelitis by XDR A. baumannii and was treated for a short period of time. Later, prosthetic aortic valve endocarditis was diagnosed. Despite treatment with cefiderocol and eravacycline, she died. An additional 18 clinical cases of IE by A. baumannii were identified from the literature, bringing the total to 19 cases. IE affected prosthetic valves in nine cases, native valves in nine and involved a right atrial mass in one. Twelve cases were caused by MDR or XDR A. baumannii. Mortality occurred more frequently in cases not treated with surgery (9/13, 69%) compared to those treated with surgery (1/6, 16.7%). However, given the very small sample size, these data should be interpreted with caution. Conclusion: This case, together with previously reported observations, highlights the severity of EI by A. baumannii and the need of multidisciplinary management. Full article

(This article belongs to the Special Issue Challenges of Multidrug-Resistant Bacteria and Drug Development of Antibacterials)

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