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Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 16735

Special Issue Editors

Dr. Silvia Zorrilla

E-Mail Website
Guest Editor
Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain
Interests: biomolecular interactions and recognition; bacterial division; bacterial membraneless compartments; bacterial transcriptional regulation; essential molecular machines; bottom-up synthetic biology; fluorescence spectroscopy; macromolecular crowding
Dr. Valentina Straniero

E-Mail Website
Guest Editor
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milan, Italy
Interests: drug discovery; medicinal chemistry, structure activity relationship; development of novel antimicrobials; FtsZ inhibitors; RnpA inhibitors; inhibition of bacterial cellular division process
Special Issues, Collections and Topics in MDPI journals
Dr. Begoña Monterroso

E-Mail Website
Guest Editor
Instituto de Química Física Blas Cabrera, CSIC, Madrid, Spain
Interests: macromolecular interactions; phase separation and microenvironments; cytometric membrane models; bacterial division; structural organization of molecular machineries; biomolecular condensates; macromolecular crowding; microfluidics

Special Issue Information

Dear Colleagues,

The discovery of antibiotics represented a substantial and significant improvement in our quality of life. Unfortunately, soon after the first antibiotic was available, bacteria surviving treatment emerged and, nowadays, resistant species can be found for almost all antibiotics, posing a growing threat to modern medicine. Moreover, multidrug-resistant bacteria are coming into play and there is increasing evidence supporting connections between bacterial infections and development of serious illnesses, such as cancer or neurodegeneration. Consequently, the scientific community is becoming more and more concerned about the need of finding new ways to fight harmful bacteria. Initiatives aiming at this end are progressively concentrating research efforts. On a broader level, involving all relevant sectors, several lines of action are being undertaken within the human-animal-environment axis in the context of One Health.

This Special Issue will be focused on the description of mechanisms used by bacteria to develop antibiotic resistance or tolerate antibiotic treatment, particularly those poorly known and/or newly proposed. Manuscripts dealing with the elucidation of crucial molecular interactions involved in essential processes for bacterial survival and proliferation, or with the development of systematic assays applicable in the quest for modulators of these interactions will also be very welcome. Submissions coming from researchers working on the development of new molecules or on the repurposing of already available compounds, reaching activity-improvement, are also expected. Articles addressing less explored approaches to fight bacterial infections, such as the use of combinations of synergic drugs, alternatives to drugs as proteins or peptides from different sources, or strategies to facilitate the access of drugs to their targets, will be also in line with the topic of this Special Issue. Original research articles, reviews, short communications or methodological reports and perspective, opinion, or commentary articles are most welcome.

Dr. Silvia Zorrilla
Dr. Valentina Straniero
Dr. Begoña Monterroso
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • molecular mechanisms of antibacterial resistance
  • essential bacterial processes
  • bacterial tolerance to antibiotics
  • emerging antibiotic targets
  • screening procedures
  • antimicrobials
  • target validation
  • drug discovery
  • drug repurposing
  • medicinal chemistry

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Published Papers (7 papers)

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Research

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13 pages, 968 KiB  
Article
Integrating Machine Learning with MALDI-TOF Mass Spectrometry for Rapid and Accurate Antimicrobial Resistance Detection in Clinical Pathogens
by Xaviera A. López-Cortés, José M. Manríquez-Troncoso, Alejandra Yáñez Sepúlveda and Patricio Suazo Soto
Int. J. Mol. Sci. 2025, 26(3), 1140; https://doi.org/10.3390/ijms26031140 - 28 Jan 2025
Cited by 1 | Viewed by 1515
Abstract
Antimicrobial resistance (AMR) is one of the most pressing public health challenges of the 21st century. This study aims to evaluate the efficacy of mass spectral data generated by VITEK® MS instruments for predicting antibiotic resistance in Staphylococcus aureus, Escherichia coli [...] Read more.
Antimicrobial resistance (AMR) is one of the most pressing public health challenges of the 21st century. This study aims to evaluate the efficacy of mass spectral data generated by VITEK® MS instruments for predicting antibiotic resistance in Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae using machine learning algorithms. Additionally, the potential of pre-trained models was assessed through transfer learning analysis. A dataset comprising 2229 mass spectra was collected, and classification algorithms, including Support Vector Machines, Random Forest, Logistic Regression, and CatBoost, were applied to predict resistance. CatBoost demonstrated a clear advantage over the other models, effectively handling complex non-linear relationships within the spectra and achieving an AUROC of 0.91 and an F1 score of 0.78 for E. coli. In contrast, transfer learning yielded suboptimal results. These findings highlight the potential of gradient-boosting techniques to enhance resistance prediction, particularly with data from less conventional platforms like VITEK® MS. Furthermore, the identification of specific biomarkers using SHAP values indicates promising potential for clinical applications in early diagnosis. Future efforts focused on standardizing data and refining algorithms could expand the utility of these approaches across diverse clinical environments, supporting the global fight against AMR. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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13 pages, 2843 KiB  
Article
Targeting Bacterial Cell Division with Benzodioxane–Benzamide FtsZ Inhibitors as a Novel Strategy to Fight Gram-Positive Ovococcal Pathogens
by Berenice Furlan, Marta Sobrinos-Sanguino, Marcella Sammartino, Begoña Monterroso, Silvia Zorrilla, Alessia Lanzini, Lorenzo Suigo, Ermanno Valoti, Orietta Massidda and Valentina Straniero
Int. J. Mol. Sci. 2025, 26(2), 714; https://doi.org/10.3390/ijms26020714 - 16 Jan 2025
Viewed by 1122
Abstract
The widespread emergence of antimicrobial resistance (AMR) is a serious threat to global public health and among Gram-positive cocci, Streptococcus pneumoniae constitutes a priority in the list of AMR-threatening pathogens. To counteract this fundamental problem, the bacterial cell division cycle and the crucial [...] Read more.
The widespread emergence of antimicrobial resistance (AMR) is a serious threat to global public health and among Gram-positive cocci, Streptococcus pneumoniae constitutes a priority in the list of AMR-threatening pathogens. To counteract this fundamental problem, the bacterial cell division cycle and the crucial proteins involved in this process emerged as novel attractive targets. FtsZ is an essential cell division protein, and FtsZ inhibitors, especially the benzamide derivatives, have been exploited in the last decade. In this work, we identified, for the first time, some benzodioxane–benzamide inhibitors capable of targeting FtsZ in Streptococcus pneumoniae, in addition to their previously demonstrated activity against other bacteria. These promising benzamides, with minimal inhibitory concentrations (MICs) ranging from 25 to 80 µg/mL, demonstrated bactericidal activity against S. pneumoniae. This was evidenced by their ability to dramatically affect growth and viability, further supported by the morphological changes observed through microscopy. Moreover, the compounds were characterized in vitro, combining turbidity measurements and confocal imaging, and significant alteration of a GTP-induced FtsZ assembly was found, in line with our previous data from other microorganisms. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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15 pages, 1681 KiB  
Article
Wounds of Companion Animals as a Habitat of Antibiotic-Resistant Bacteria That Are Potentially Harmful to Humans—Phenotypic, Proteomic and Molecular Detection
by Anna Lenart-Boroń, Klaudia Stankiewicz, Natalia Czernecka, Anna Ratajewicz, Klaudia Bulanda, Miłosz Heliasz, Daria Sosińska, Kinga Dworak, Dominika Ciesielska, Izabela Siemińska and Marek Tischner
Int. J. Mol. Sci. 2024, 25(6), 3121; https://doi.org/10.3390/ijms25063121 - 8 Mar 2024
Cited by 8 | Viewed by 2252
Abstract
Skin wounds and their infections by antibiotic-resistant bacteria (ARB) are very common in small animals, posing the risk of acquiring ARB by pet owners or antibiotic resistance gene (ARG) transfer to the owners’ microbiota. The aim of this study was to identify the [...] Read more.
Skin wounds and their infections by antibiotic-resistant bacteria (ARB) are very common in small animals, posing the risk of acquiring ARB by pet owners or antibiotic resistance gene (ARG) transfer to the owners’ microbiota. The aim of this study was to identify the most common pathogens infecting wounds of companion animals, assess their antibiotic resistance, and determine the ARGs using culture-based, molecular, and proteomic methods. A total of 136 bacterial strains were isolated from wound swabs. Their species was identified using chromogenic media, followed by MALDI-TOF spectrometry. Antibiotic resistance was tested using disc diffusion, and twelve ARGs were detected using PCRs. The dominant species included Staphylococcus pseudintermedius (9.56%), E. coli, and E. faecalis (both n = 11, 8.09%). Enterobacterales were mostly resistant to amoxicillin/clavulanic acid (68.3% strains), all Pseudomonas were resistant to ceftazidime, piperacillin/tazobactam, imipenem, and tylosin, Acinetobacter were mostly resistant to tylosin (55.5%), all Enterococcus were resistant to imipenem, and 39.2% of Staphylococci were resistant to clindamycin. Among ARGs, strA (streptomycin resistance), sul3 (sulfonamide resistance), and blaTEM, an extended-spectrum beta-lactamase determinant, were the most frequent. The risk of ARB and ARG transfer between animals and humans causes the need to search for new antimicrobial therapies in future veterinary medicine. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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13 pages, 1829 KiB  
Article
Drug Repositioning as a Therapeutic Strategy against Streptococcus pneumoniae: Cell Membrane as Potential Target
by Laura Ortiz-Miravalles, Manuel Sánchez-Angulo, Jesús M. Sanz and Beatriz Maestro
Int. J. Mol. Sci. 2023, 24(6), 5831; https://doi.org/10.3390/ijms24065831 - 18 Mar 2023
Cited by 5 | Viewed by 3039
Abstract
A collection of repurposing drugs (Prestwick Chemical Library) containing 1200 compounds was screened to investigate the drugs’ antimicrobial effects against planktonic cultures of the respiratory pathogen Streptococcus pneumoniae. After four discrimination rounds, a set of seven compounds was finally selected, namely (i) [...] Read more.
A collection of repurposing drugs (Prestwick Chemical Library) containing 1200 compounds was screened to investigate the drugs’ antimicrobial effects against planktonic cultures of the respiratory pathogen Streptococcus pneumoniae. After four discrimination rounds, a set of seven compounds was finally selected, namely (i) clofilium tosylate; (ii) vanoxerine; (iii) mitoxantrone dihydrochloride; (iv) amiodarone hydrochloride; (v) tamoxifen citrate; (vi) terfenadine; and (vii) clomiphene citrate (Z, E). These molecules arrested pneumococcal growth in a liquid medium and induced a decrease in bacterial viability between 90.0% and 99.9% at 25 µM concentration, with minimal inhibitory concentrations (MICs) also in the micromolar range. Moreover, all compounds but mitoxantrone caused a remarkable increase in the permeability of the bacterial membrane and share a common, minimal chemical structure consisting of an aliphatic amine linked to a phenyl moiety via a short carbon/oxygen linker. These results open new possibilities to tackle pneumococcal disease through drug repositioning and provide clues for the design of novel membrane-targeted antimicrobials with a related chemical structure. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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Review

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15 pages, 3739 KiB  
Review
Knowing Our Enemy in the Antimicrobial Resistance Era: Dissecting the Molecular Basis of Bacterial Defense Systems
by Mario Martínez, Irene Rizzuto and Rafael Molina
Int. J. Mol. Sci. 2024, 25(9), 4929; https://doi.org/10.3390/ijms25094929 - 30 Apr 2024
Cited by 1 | Viewed by 2199
Abstract
Bacteria and their phage adversaries are engaged in an ongoing arms race, resulting in the development of a broad antiphage arsenal and corresponding viral countermeasures. In recent years, the identification and utilization of CRISPR–Cas systems have driven a renewed interest in discovering and [...] Read more.
Bacteria and their phage adversaries are engaged in an ongoing arms race, resulting in the development of a broad antiphage arsenal and corresponding viral countermeasures. In recent years, the identification and utilization of CRISPR–Cas systems have driven a renewed interest in discovering and characterizing antiphage mechanisms, revealing a richer diversity than initially anticipated. Currently, these defense systems can be categorized based on the bacteria’s strategy associated with the infection cycle stage. Thus, bacterial defense systems can degrade the invading genetic material, trigger an abortive infection, or inhibit genome replication. Understanding the molecular mechanisms of processes related to bacterial immunity has significant implications for phage-based therapies and the development of new biotechnological tools. This review aims to comprehensively cover these processes, with a focus on the most recent discoveries. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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20 pages, 2045 KiB  
Review
One Earth: The Equilibrium between the Human and the Bacterial Worlds
by Alicia Bravo, Ana Moreno-Blanco and Manuel Espinosa
Int. J. Mol. Sci. 2023, 24(20), 15047; https://doi.org/10.3390/ijms242015047 - 10 Oct 2023
Cited by 6 | Viewed by 2202
Abstract
Misuse and abuse of antibiotics on humans, cattle, and crops have led to the selection of multi-resistant pathogenic bacteria, the most feared ‘superbugs’. Infections caused by superbugs are progressively difficult to treat, with a subsequent increase in lethality: the toll on human lives [...] Read more.
Misuse and abuse of antibiotics on humans, cattle, and crops have led to the selection of multi-resistant pathogenic bacteria, the most feared ‘superbugs’. Infections caused by superbugs are progressively difficult to treat, with a subsequent increase in lethality: the toll on human lives is predicted to reach 10 million by 2050. Here we review three concepts linked to the growing resistance to antibiotics, namely (i) the Resistome, which refers to the collection of bacterial genes that confer resistance to antibiotics, (ii) the Mobilome, which includes all the mobile genetic elements that participate in the spreading of antibiotic resistance among bacteria by horizontal gene transfer processes, and (iii) the Nichome, which refers to the set of genes that are expressed when bacteria try to colonize new niches. We also discuss the strategies that can be used to tackle bacterial infections and propose an entente cordiale with the bacterial world so that instead of war and destruction of the ‘fierce enemy’ we can achieve a peaceful coexistence (the One Earth concept) between the human and the bacterial worlds. This, in turn, will contribute to microbial biodiversity, which is crucial in a globally changing climate due to anthropogenic activities. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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19 pages, 2677 KiB  
Review
Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?
by Giovanni Stelitano, Mario Cocorullo, Matteo Mori, Stefania Villa, Fiorella Meneghetti and Laurent Roberto Chiarelli
Int. J. Mol. Sci. 2023, 24(7), 6181; https://doi.org/10.3390/ijms24076181 - 24 Mar 2023
Cited by 13 | Viewed by 2938
Abstract
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we [...] Read more.
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue. Full article
(This article belongs to the Special Issue Novel Mechanisms of Bacterial Antibiotic Resistance and Strategies to Fight Them)
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