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Pharmaceuticals
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Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria
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Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 10726

Special Issue Editor

Dr. Adriána Liptáková

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Guest Editor
Institute of Microbiology, Faculty of Medicine, University Hospital Bratislava, Comenius University, 81108 Bratislava, Slovakia
Interests: drug-resistant bacteria; antimicrobial resistance; new therapeutic solutions; improvement of existing therapies and alternative therapies, such as autovaccines or bacteriophage therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antimicrobial resistance is responsible for more than 35,000 deaths per year in the EU/EEA and imposes significant costs, particularly on healthcare systems. In July 2022 the Commission, together with the Member States, recognized antimicrobial resistance as one of the most serious health threats. Overall, recent data suggest a significant upward trend in infections and associated deaths in almost all combinations of ‘antibiotic resistance’, particularly in healthcare settings. The consequence of the use of antibiotics is not only the selection of antibiotic-resistant microorganisms, but also a negative impact on the human body as a whole in the form of various side effects. Since the constant growth of the antibiotic resistance of microorganisms is becoming a global problem, the development of new therapeutic solutions, including alternatives to antimicrobial drugs, or the improvement of existing ones is urgently needed.

What are the best next steps? Are there promising clinical trials that keep in mind the serious expectation that antimicrobial resistance (AMR) will kill up to 10 million people a year by 2050? Sharing your research and your thoughts can solve this major healthcare issue.

Dr. Adriána Liptáková
Guest Editor

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Keywords

  • development of antibacterial drugs
  • drug-resistant bacteria
  • antimicrobial resistance
  • new therapeutic solutions
  • improvement of existing therapies
  • nosocomial infections

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Published Papers (7 papers)

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Research

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19 pages, 2212 KiB  
Article
Highlighting the Potential of LyeTx I, a Peptide Derived from the Venom of the Spider Lycosa erythrognatha, as a Potential Prototype for the Development of a New Antimicrobial Against Carbapenem-Resistant Klebsiella pneumoniae
by William Gustavo Lima, Amanda Souza Félix, Felipe Rocha da Silva Santos, Fernanda de Lima Tana, Amanda Neves de Souza, Rodrigo Moreira Verly and Maria Elena de Lima
Pharmaceuticals 2025, 18(5), 679; https://doi.org/10.3390/ph18050679 - 2 May 2025
Viewed by 101
Abstract
Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a multidrug-resistant (MDR) gram-negative bacterium frequently involved in hospital-acquired pneumonia. The infection caused by this superbug has spread quickly in health centers worldwide, leading to high mortality rates. Due to this emerging scenario, the World Health [...] Read more.
Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a multidrug-resistant (MDR) gram-negative bacterium frequently involved in hospital-acquired pneumonia. The infection caused by this superbug has spread quickly in health centers worldwide, leading to high mortality rates. Due to this emerging scenario, the World Health Organization has categorized CRKP as the highest-priority species for the development of new compounds. In this context, antimicrobial peptides (AMPs) stand out as prototypes for alternative antimicrobials against superbugs, including CRKP. Objectives: We aimed to describe the antibacterial effect of an AMP (LyeTx I), derived from the venom of the spider Lycosa erythrognatha, against CRKP in vitro and in a murine pneumonia model. Results: LyeTx I showed antibacterial effects against all the CRKP clinical isolates tested, with a minimum inhibitory concentration (MIC) range of 2–8 µM and a minimum bactericidal concentration (MBC) range of 2–16 µM. The microbial anionic membrane was the primary target of LyeTx I, which acts by displacing divalent cations bound to this structure in a manner similar to that of polymyxins. Notably, LyeTx I displayed significant lytic activity against mimetic membranes, indicating its potential to disrupt bacterial cell integrity. In in vivo assays, the LyeTx I peptide proved to be safe at a dose of 10 mg/kg. In addition, intraperitoneal use of LyeTx I reduced the bacterial load and inflammation in the lungs of animals infected with a hypervirulent strain of CRKP. Conclusions: These results indicate that LyeTx I is a potential prototype for the development of new antibacterials against MDR species, such as CRKP. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
14 pages, 3892 KiB  
Article
Evaluation of the Efflux Pump Inhibition Activity of Thiadiazine-Derived Compounds Against the Staphylococcus aureus 1199B Strain
by Cicera Laura Roque Paulo, Priscilla Ramos Freitas Alexandre, Ana Carolina Ferreira Araujo, Ray Silva Almeida, Emílio Sousa Albuquerque, Cícera Datiane de Morais Oliveira-Tintino, Igor J. S. Nascimento, João Xavier Araújo-Júnior, Edeildo Ferreira da Silva-Junior, Thiago Mendonça de Aquino, Francisco Jaime Bezerra Mendonça-Junior, José Bezerra de Araújo-Neto, Maria Karollyna do Nascimento Silva Leandro, Irwin Rose Alencar de Menezes, Henrique Douglas Melo Coutinho and Janaina Esmeraldo Rocha
Pharmaceuticals 2025, 18(3), 323; https://doi.org/10.3390/ph18030323 - 25 Feb 2025
Viewed by 370
Abstract
Background: Substances with antibacterial properties have become crucial in light of the continuous increase in infections caused by multidrug-resistant bacteria. In this context, thiadiazines have emerged as heterocyclic compounds already known for their pharmacological activities. However, their potential as antibacterial agents and inhibitors [...] Read more.
Background: Substances with antibacterial properties have become crucial in light of the continuous increase in infections caused by multidrug-resistant bacteria. In this context, thiadiazines have emerged as heterocyclic compounds already known for their pharmacological activities. However, their potential as antibacterial agents and inhibitors of the efflux system found in resistant bacteria remains poorly understood. From this perspective, the present study highlights the synthesis of thiadiazine-derived compounds and evaluates their antibacterial activity and efflux pump inhibition against the Staphylococcus aureus 1199B strain. Methods: To this end, Minimum Inhibitory Concentration (MIC) tests were conducted, along with the analysis of antibacterial activity through the inhibition of the NorA efflux system using 96-well microdilution assays. Additionally, to assess efflux system inhibition, ethidium bromide (EtBr) fluorescence emission tests were performed, alongside in silico molecular docking studies. Results: Based on the results obtained, it was observed that compound IJ28 exhibited direct activity against the tested SA 1199B strains, with an MIC of 512 µg/mL. It also demonstrated antibacterial activity through efflux pump inhibition, resulting in increased fluorescence rates emitted by EtBr. Compound IJ28 showed a more significant reduction in the Minimum Inhibitory Concentration (MIC) of ethidium bromide, decreasing from 26.6 µg/mL to 0.5 µg/mL, compared to the other compounds. Conclusions: Therefore, it is essential to conduct further studies to investigate the mechanism of action and clarify the feasibility and effects of compound IJ28 as a potential antibacterial agent. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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19 pages, 11771 KiB  
Article
In Silico Study of the Potential Inhibitory Effects on Escherichia coli DNA Gyrase of Some Hypothetical Fluoroquinolone–Tetracycline Hybrids
by Ioana-Andreea Lungu, Octavia-Laura Oancea and Aura Rusu
Pharmaceuticals 2024, 17(11), 1540; https://doi.org/10.3390/ph17111540 - 16 Nov 2024
Viewed by 1334
Abstract
Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines [...] Read more.
Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines are versatile antibiotics that are effective against various bacterial infections. A hybrid antibiotic combines two or more molecules to enhance antimicrobial effectiveness and combat resistance better than monotherapy. Fluoroquinolones are ideal candidates for hybridization due to their potent bactericidal effects, ease of synthesis, and ability to form combinations with other molecules. Methods: This study explored the mechanisms of action for 40 hypothetical fluoroquinolone–tetracycline hybrids, all of which could be obtained using a simple, eco-friendly synthesis method. Their interaction with Escherichia coli DNA Gyrase and similarity to albicidin were evaluated using the FORECASTER platform. Results: Hybrids such as Do-Ba, Mi-Fi, and Te-Ba closely resembled albicidin in physicochemical properties and FITTED Scores, while Te-De surpassed it with a better score. Similar to fluoroquinolones, these hybrids likely inhibit DNA synthesis by binding to enzyme–DNA complexes. Conclusions: These hybrids could offer broad-spectrum activity and help mitigate bacterial resistance, though further in vitro and in vivo studies are needed to validate their potential. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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25 pages, 3412 KiB  
Article
Is It Time to Start Worrying? A Comprehensive Report on the Three-Year Prevalence of ESBL-Producing Bacteria and Their Trends in Antibiotic Resistance from the Largest University Hospital in Slovakia
by Yashar Jalali, Andrea Kološová, Adriána Liptáková, Ján Kyselovič, Anna Oleárová, Monika Jalali and Juraj Payer
Pharmaceuticals 2024, 17(11), 1517; https://doi.org/10.3390/ph17111517 - 11 Nov 2024
Viewed by 1474
Abstract
Background/Objectives: Over the past few decades, extended-spectrum β-lactamase (ESBL)-producing bacteria have become a great concern in healthcare systems worldwide, imposing large burdens by increasing antimicrobial resistance and patient morbidity. Given the high mortality rates and emergence of multidrug-resistant (MDR) strains, monitoring ESBL prevalence [...] Read more.
Background/Objectives: Over the past few decades, extended-spectrum β-lactamase (ESBL)-producing bacteria have become a great concern in healthcare systems worldwide, imposing large burdens by increasing antimicrobial resistance and patient morbidity. Given the high mortality rates and emergence of multidrug-resistant (MDR) strains, monitoring ESBL prevalence and resistance patterns is crucial. This study aimed to evaluate ESBL-producing Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae over three years, focusing on phenotypic distribution and resistance profiles. Methods: A total of 1599 ESBL-producing bacterial samples were collected and analysed. A panel of 20 antibiotics was tested to determine resistance traits. Data were recorded on phenotypical distribution, isolation types, changes in antibiotic resistance, and the relation of such changes to antibiotic consumption (defined daily dose) from clinical isolates. Results: Phenotypical analysis revealed the minimal presence of the Cefotaximase from Munich (CTX-M) phenotype in E. coli and K. pneumoniae, creating a distinct epidemiological profile compared to global patterns. Shifts in isolation trends, particularly in P. mirabilis, suggest an expected increase in associated-mortality-rate in the coming years. While resistance trends were not statistically significant, MDR and extensively drug-resistant (XDR) strains were identified across all three bacteria. Only meropenem showed consistent 100% efficacy against E. coli, with other antibiotics displaying only partial effectiveness. Conclusions: These findings highlight the need for ongoing surveillance of ESBL-producing bacteria and underscore challenges in managing antibiotic resistance due to limited efficacy of last-resort treatments. The unique phenotypical distribution observed could impact local resistance management strategies in hospital settings in the coming years. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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18 pages, 1852 KiB  
Article
Ceragenins Prevent the Development of Murine Vaginal Infection Caused by Gardnerella vaginalis
by Urszula Wnorowska, Ewelina Piktel, Tamara Daniluk, Paulina Paprocka, Paul B. Savage, Bonita Durnaś and Robert Bucki
Pharmaceuticals 2024, 17(11), 1445; https://doi.org/10.3390/ph17111445 - 29 Oct 2024
Viewed by 1254
Abstract
Background/Objectives: Bacterial vaginosis (BV), an infection caused primarily by Gardnerella vaginalis, is the most prevalent vaginal infection. Although BV is often characterized by an asymptomatic course, it can lead to considerable health complications. Currently, BV therapy choices are limited, and available treatments [...] Read more.
Background/Objectives: Bacterial vaginosis (BV), an infection caused primarily by Gardnerella vaginalis, is the most prevalent vaginal infection. Although BV is often characterized by an asymptomatic course, it can lead to considerable health complications. Currently, BV therapy choices are limited, and available treatments are complicated by concerns about antibiotic resistance. Ceragenins, which together comprise an innovative class of low molecular-weight, cholic acid-based antibacterial agents, have emerged as potential alternatives to conventional treatments. Methods: This study investigates (i) the antibacterial activity of ceragenins against G. vaginalis in in vitro experimental settings at varied pH, and (ii) the effectiveness and anti-inflammatory properties of CSA-13 in a G. vaginalis-induced bacterial vaginosis animal model. Results and Conclusions: We demonstrate that ceragenins, particularly CSA-13, maintain their antibacterial efficacy throughout pH range of 4.5–7, with the highest activity observed at neutral pH (7.0). Additionally, in an animal model, beneficial effects of ceragenins are attributed to anti-inflammatory properties of these compounds, making these compounds promising agents as potential new treatment options against G. vaginalis-associated vaginal infections. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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Review

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25 pages, 3507 KiB  
Review
Transmission Dynamics and Novel Treatments of High Risk Carbapenem-Resistant Klebsiella pneumoniae: The Lens of One Health
by Jiaying Zhu, Taoyu Chen, Yanmin Ju, Jianjun Dai and Xiangkai Zhuge
Pharmaceuticals 2024, 17(9), 1206; https://doi.org/10.3390/ph17091206 - 12 Sep 2024
Cited by 8 | Viewed by 3854
Abstract
The rise of antibiotic resistance and the dwindling antimicrobial pipeline have emerged as significant threats to public health. The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a global threat, with limited options available for targeted therapy. The CRKP has experienced various changes and [...] Read more.
The rise of antibiotic resistance and the dwindling antimicrobial pipeline have emerged as significant threats to public health. The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a global threat, with limited options available for targeted therapy. The CRKP has experienced various changes and discoveries in recent years regarding its frequency, transmission traits, and mechanisms of resistance. In this comprehensive review, we present an in-depth analysis of the global epidemiology of K. pneumoniae, elucidate resistance mechanisms underlying its spread, explore evolutionary dynamics concerning carbapenem-resistant hypervirulent strains as well as KL64 strains of K. pneumoniae, and discuss recent therapeutic advancements and effective control strategies while providing insights into future directions. By going through up-to-date reports, we found that the ST11 KL64 CRKP subclone with high risk demonstrated significant potential for expansion and survival benefits, likely due to genetic influences. In addition, it should be noted that phage and nanoparticle treatments still pose significant risks for resistance development; hence, innovative infection prevention and control initiatives rooted in One Health principles are advocated as effective measures against K. pneumoniae transmission. In the future, further imperative research is warranted to comprehend bacterial resistance mechanisms by focusing particularly on microbiome studies’ application and implementation of the One Health strategy. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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19 pages, 4132 KiB  
Review
In Vitro Resistance-Predicting Studies and In Vitro Resistance-Related Parameters—A Hit-to-Lead Perspective
by Joanna Krajewska, Stefan Tyski and Agnieszka E. Laudy
Pharmaceuticals 2024, 17(8), 1068; https://doi.org/10.3390/ph17081068 - 15 Aug 2024
Cited by 1 | Viewed by 1577
Abstract
Despite the urgent need for new antibiotics, very few innovative antibiotics have recently entered clinics or clinical trials. To provide a constant supply of new drug candidates optimized in terms of their potential to select for resistance in natural settings, in vitro resistance-predicting [...] Read more.
Despite the urgent need for new antibiotics, very few innovative antibiotics have recently entered clinics or clinical trials. To provide a constant supply of new drug candidates optimized in terms of their potential to select for resistance in natural settings, in vitro resistance-predicting studies need to be improved and scaled up. In this review, the following in vitro parameters are presented: frequency of spontaneous mutant selection (FSMS), mutant prevention concentration (MPC), dominant mutant prevention concentration (MPC-D), inferior-mutant prevention concentration (MPC-F), and minimal selective concentration (MSC). The utility of various adaptive laboratory evolution (ALE) approaches (serial transfer, continuous culture, and evolution in spatiotemporal microenvironments) for comparing hits in terms of the level and time required for multistep resistance to emerge is discussed. We also consider how the hit-to-lead stage can benefit from high-throughput ALE setups based on robotic workstations, do-it-yourself (DIY) continuous cultivation systems, microbial evolution and growth arena (MEGA) plates, soft agar gradient evolution (SAGE) plates, microfluidic chips, or microdroplet technology. Finally, approaches for evaluating the fitness of in vitro-generated resistant mutants are presented. This review aims to draw attention to newly emerged ideas on how to improve the in vitro forecasting of the potential of compounds to select for resistance in natural settings. Full article
(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)
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