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Pathogens
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Drugs Repurposing for Multi-Drug Resistant Bacterial Infections
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Drugs Repurposing for Multi-Drug Resistant Bacterial Infections

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 23042

Special Issue Editors

Dr. Maytham Hussein

E-Mail Website
Guest Editor
Faculty of Medicine, Dentistry and Health Sciences, Melbourne, Australia
Interests: antimicrobial resistance; system pharmacology; antibiotics discovery and development
Dr. Tony Velkov

E-Mail Website
Guest Editor
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, Australia
Interests: antimicrobial resistance; system pharmacology; antibiotics discovery and development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multidrug-resistant (MDR) bacteria are becoming a major burden for public health systems worldwide. The excessive and inappropriate use of antibiotics following antibiotic discoveries has led to the development of numerous MDR bacteria. This issue is further compounded by the exodus of many pharmaceutical companies from the antibiotics discovery industry due to lengthy and unreliable  product development processes and low economic returns. In order to prevent resistance against conventional antibiotics, novel application approaches need to be considered as the development of new antibiotics is still beyond the horizon.  Combining antibiotic and non-antibiotic drugs for improved efficacy and to delay the inevitable development of bacterial resistance has thus emerged as a cost-effective approach to fighting MDR bacteria.

We welcome the submission of reviews, opinions, and original research focusing on drug re-purposing for treatment against bacteria.

Dr. Maytham Hussein
Dr. Tony Velkov
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 100 words) can be sent to the Editorial Office for announcement on this website.

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. 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 2200 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

  • bacterial infections
  • antimicrobials
  • drug re-purposing
  • antimicrobial resistance

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Published Papers (6 papers)

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Research

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12 pages, 1387 KiB  
Article
Artemisia afra and Artemisia annua Extracts Have Bactericidal Activity against Mycobacterium tuberculosis in Physiologically Relevant Carbon Sources and Hypoxia
by Bushra Hafeez Kiani, Maria Natalia Alonso, Pamela J. Weathers and Scarlet S. Shell
Pathogens 2023, 12(2), 227; https://doi.org/10.3390/pathogens12020227 - 1 Feb 2023
Cited by 5 | Viewed by 3414
Abstract
Mycobacterium tuberculosis (Mtb) is a deadly pathogen and causative agent of human tuberculosis, causing ~1.5 million deaths every year. The increasing drug resistance of this pathogen necessitates novel and improved treatment strategies. A crucial aspect of the host–pathogen interaction is bacterial nutrition. In [...] Read more.
Mycobacterium tuberculosis (Mtb) is a deadly pathogen and causative agent of human tuberculosis, causing ~1.5 million deaths every year. The increasing drug resistance of this pathogen necessitates novel and improved treatment strategies. A crucial aspect of the host–pathogen interaction is bacterial nutrition. In this study, Artemisia annua and Artemisia afra dichloromethane extracts were tested for bactericidal activity against Mtb strain mc26230 under hypoxia and various infection-associated carbon sources (glycerol, glucose, and cholesterol). Both extracts showed significant bactericidal activity against Mtb, regardless of carbon source. Based on killing curves, A. afra showed the most consistent bactericidal activity against Mtb for all tested carbon sources, whereas A. annua showed the highest bactericidal activity in 7H9 minimal media with glycerol. Both extracts retained their bactericidal activity against Mtb under hypoxic conditions. Further investigations are required to determine the mechanism of action of these extracts and identify their active constituent compounds. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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14 pages, 3018 KiB  
Article
Sodium Malonate Inhibits the AcrAB-TolC Multidrug Efflux Pump of Escherichia coli and Increases Antibiotic Efficacy
by Allea Cauilan and Cristian Ruiz
Pathogens 2022, 11(12), 1409; https://doi.org/10.3390/pathogens11121409 - 24 Nov 2022
Cited by 4 | Viewed by 3099
Abstract
There is an urgent need to find novel treatments for combating multidrug-resistant bacteria. Multidrug efflux pumps that expel antibiotics out of cells are major contributors to this problem. Therefore, using efflux pump inhibitors (EPIs) is a promising strategy to increase antibiotic efficacy. However, [...] Read more.
There is an urgent need to find novel treatments for combating multidrug-resistant bacteria. Multidrug efflux pumps that expel antibiotics out of cells are major contributors to this problem. Therefore, using efflux pump inhibitors (EPIs) is a promising strategy to increase antibiotic efficacy. However, there are no EPIs currently approved for clinical use especially because of their toxicity. This study investigates sodium malonate, a natural, non-hazardous, small molecule, for its use as a novel EPI of AcrAB-TolC, the main multidrug efflux pump of the Enterobacteriaceae family. Using ethidium bromide accumulation experiments, we found that 25 mM sodium malonate inhibited efflux by the AcrAB-TolC and other MDR pumps of Escherichia coli to a similar degree than 50 μΜ phenylalanine-arginine-β-naphthylamide, a well-known EPI. Using minimum inhibitory concentration assays and molecular docking to study AcrB-ligand interactions, we found that sodium malonate increased the efficacy of ethidium bromide and the antibiotics minocycline, chloramphenicol, and ciprofloxacin, possibly via binding to multiple AcrB locations, including the AcrB proximal binding pocket. In conclusion, sodium malonate is a newly discovered EPI that increases antibiotic efficacy. Our findings support the development of malonic acid/sodium malonate and its derivatives as promising EPIs for augmenting antibiotic efficacy when treating multidrug-resistant bacterial infections. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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12 pages, 2465 KiB  
Article
Synergistic Antibiofilm Activity between Synthetic Peptides and Ciprofloxacin against Staphylococcus aureus
by Nilton A. S. Neto, Jose T. A. Oliveira, Tawanny K. B. Aguiar, Leandro P. Bezerra, Levi A. C. Branco, Felipe P. Mesquita, Cleverson D. T. Freitas and Pedro F. N. Souza
Pathogens 2022, 11(9), 995; https://doi.org/10.3390/pathogens11090995 - 31 Aug 2022
Cited by 5 | Viewed by 2170
Abstract
Staphylococcus aureus is a human pathogen known to be resistant to antibiotics since the mid-20th century and is constantly associated with hospital-acquired infections. S. aureus forms biofilms, which are complex surface-attached communities of bacteria held together by a self-produced polymer matrix consisting of [...] Read more.
Staphylococcus aureus is a human pathogen known to be resistant to antibiotics since the mid-20th century and is constantly associated with hospital-acquired infections. S. aureus forms biofilms, which are complex surface-attached communities of bacteria held together by a self-produced polymer matrix consisting of proteins, extracellular DNA, and polysaccharides. Biofilms are resistance structures responsible for increasing bacterial resistance to drugs by 1000 times more than the planktonic lifestyle. Therefore, studies have been conducted to discover novel antibacterial molecules to prevent biofilm formation and/or degrade preformed biofilms. Synthetic antimicrobial peptides (SAMPs) have appeared as promising alternative agents to overcome increasing antibiotic resistance. Here, the antibiofilm activity of eight SAMPs, in combination with the antibiotic ciprofloxacin, was investigated in vitro. Biofilm formation by S. aureus was best inhibited (76%) by the combination of Mo-CBP3-PepIII (6.2 µg mL−1) and ciprofloxacin (0.39 µg mL−1). In contrast, the highest reduction (60%) of the preformed biofilm mass was achieved with RcAlb-PepII (1.56 µg mL−1) and ciprofloxacin (0.78 µg mL−1). Fluorescence microscopy analysis reinforced these results. These active peptides formed pores in the cellular membrane of S. aureus, which may be related to the enhanced ciprofloxacin’s antibacterial activity. Our findings indicated that these peptides may act with ciprofloxacin and are powerful co-adjuvant agents for the treatment of S. aureus infections. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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16 pages, 4213 KiB  
Article
Polymyxin B in Combination with Glycerol Monolaurate Exerts Synergistic Killing against Gram-Negative Pathogens
by Yun Zheng, Ning Yang, Yuting Ding, Jiajia Li, Yanyan Liu, Haoran Chen and Jiabin Li
Pathogens 2022, 11(8), 874; https://doi.org/10.3390/pathogens11080874 - 2 Aug 2022
Cited by 3 | Viewed by 2051
Abstract
The rapid emergence and spread of multidrug-resistant (MDR) bacterial pathogens pose a serious danger to worldwide human health, and resistance to last-resort drugs, such as polymyxins, is being increasingly detected in MDR Gram-negative pathogens. There is an urgent need to find and optimize [...] Read more.
The rapid emergence and spread of multidrug-resistant (MDR) bacterial pathogens pose a serious danger to worldwide human health, and resistance to last-resort drugs, such as polymyxins, is being increasingly detected in MDR Gram-negative pathogens. There is an urgent need to find and optimize combination therapies as an alternative therapeutic strategy, with a dry pipeline in novel antibiotic research and development. We found a monoester formed from the combination of lauric acid and glycerol, glycerol monolaurate (GML), possessing prominent antibacterial and anti-inflammatory activity. However, it is still unclear whether GML in combination could increase antimicrobial activity. Here, we reported that polymyxin B (PMNB) combined with GML exhibited a synergistic antimicrobial impact on Gram-negative strains in vitro, including clinical MDR isolates. This synergistic antimicrobial activity correlated with the destruction of bacterial cell structures, eradication of preformed biofilms, and increased reactive oxygen species (ROS) accumulation. We also showed that PMNB synergized with GML effectively eliminated pathogens from bacterial pneumonia caused by Klebsiella pneumoniae to rescue mice. Our research demonstrated that the PMNB and GML combination induced synergistic antimicrobial activity for Gram-negative pathogens in vitro and in vivo. These findings are of great importance for treating bacterial infections and managing the spread of infectious diseases. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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Review

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20 pages, 6954 KiB  
Review
Drug Repurposing Approaches towards Defeating Multidrug-Resistant Gram-Negative Pathogens: Novel Polymyxin/Non-Antibiotic Combinations
by Augustine Koh Jing Jie, Maytham Hussein, Gauri G. Rao, Jian Li and Tony Velkov
Pathogens 2022, 11(12), 1420; https://doi.org/10.3390/pathogens11121420 - 25 Nov 2022
Cited by 13 | Viewed by 3485
Abstract
Multidrug-resistant (MDR) Gram-negative pathogens remain an unmet public health threat. In recent times, increased rates of resistance have been reported not only to commonly used antibiotics, but also to the last-resort antibiotics, such as polymyxins. More worryingly, despite the current trends in resistance, [...] Read more.
Multidrug-resistant (MDR) Gram-negative pathogens remain an unmet public health threat. In recent times, increased rates of resistance have been reported not only to commonly used antibiotics, but also to the last-resort antibiotics, such as polymyxins. More worryingly, despite the current trends in resistance, there is a lack of new antibiotics in the drug-discovery pipeline. Hence, it is imperative that new strategies are developed to preserve the clinical efficacy of the current antibiotics, particularly the last-line agents. Combining conventional antibiotics such as polymyxins with non-antibiotics (or adjuvants), has emerged as a novel and effective strategy against otherwise untreatable MDR pathogens. This review explores the available literature detailing the latest polymyxin/non-antibiotic combinations, their mechanisms of action, and potential avenues to advance their clinical application. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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17 pages, 1781 KiB  
Review
Host-Directed Therapies for Tuberculosis
by Eui-Kwon Jeong, Hyo-Ji Lee and Yu-Jin Jung
Pathogens 2022, 11(11), 1291; https://doi.org/10.3390/pathogens11111291 - 3 Nov 2022
Cited by 12 | Viewed by 7985
Abstract
Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, [...] Read more.
Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action. Full article
(This article belongs to the Special Issue Drugs Repurposing for Multi-Drug Resistant Bacterial Infections)
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