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Antibiotics
Special Issues
Drugs Repurposing for the Treatment of Bacterial Infections
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Drugs Repurposing for the Treatment of Bacterial Infections

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 72287

Special Issue Editor

Dr. Younes Smani

E-Mail Website
Guest Editor
Institute of Biomedicine of Seville, University of Seville, 41013 Seville, Spain
Interests: antimicrobial resistance; bacterial pathogenesis; antibiotics; repurposing drug; non-traditional approaches
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multidrug-resistant (MDR) pathogens pose a well-recognized global health threat that demands effective solutions: in fact, the situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the 10 million deaths predicted to occur by 2050 as a result of MDR bacteria. The repurposing of drugs as therapeutic alternatives for infections has recently gained renewed interest. As drugs approved by the United States Food and Drug Administration, information about their pharmacological characteristics in preclinical and clinical trials is available. Therefore, the time and economic costs required to evaluate these drugs for other therapeutic applications, such as the treatment of bacterial infections, are mitigated. The goal of this Special Issue is to provide an overview of the scientific evidence on potential non-antimicrobial drugs targeting bacteria. In particular, we aim to: (i) List the approved drugs identified in drug screens as potential alternative treatments for infections caused by MDR bacteria; (ii) Review their mechanisms of action against bacteria; (iii) Summarize the outcome of preclinical and clinical trials investigating approved drugs that target these bacteria.

Dr. Younes Smani
Guest Editor

Manuscript Submission Information

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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

  • repurposing drugs
  • treatment
  • antimicrobial resistance
  • infection
  • bacteria

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Published Papers (7 papers)

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Research

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22 pages, 3717 KiB  
Article
Repurposing Disulfiram (Tetraethylthiuram Disulfide) as a Potential Drug Candidate against Borrelia burgdorferi In Vitro and In Vivo
by Hari-Hara S. K. Potula, Jahanbanoo Shahryari, Mohammed Inayathullah, Andrey Victorovich Malkovskiy, Kwang-Min Kim and Jayakumar Rajadas
Antibiotics 2020, 9(9), 633; https://doi.org/10.3390/antibiotics9090633 - 22 Sep 2020
Cited by 21 | Viewed by 7335
Abstract
Lyme disease caused by the Borrelia burgdorferi (Bb or B. burgdorferi) is the most common vector-borne, multi-systemic disease in the USA. Although most Lyme disease patients can be cured with a course of the first line of antibiotic treatment, some patients [...] Read more.
Lyme disease caused by the Borrelia burgdorferi (Bb or B. burgdorferi) is the most common vector-borne, multi-systemic disease in the USA. Although most Lyme disease patients can be cured with a course of the first line of antibiotic treatment, some patients are intolerant to currently available antibiotics, necessitating the development of more effective therapeutics. We previously found several drugs, including disulfiram, that exhibited effective activity against B. burgdorferi. In the current study, we evaluated the potential of repurposing the FDA-approved drug, disulfiram for its borreliacidal activity. Our results indicate disulfiram has excellent borreliacidal activity against both the log and stationary phase B. burgdorferi sensu stricto B31 MI. Treatment of mice with disulfiram eliminated the B. burgdorferi sensu stricto B31 MI completely from the hearts and urinary bladder by day 28 post infection. Moreover, disulfiram-treated mice showed reduced expressions of inflammatory markers, and thus they were protected from histopathology and cardiac organ damage. Furthermore, disulfiram-treated mice showed significantly lower amounts of total antibody titers (IgM and IgG) at day 21 and total IgG2b at day 28 post infection. FACS analysis of lymph nodes revealed a decrease in the percentage of CD19+ B cells and an increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naive and effector memory cells in disulfiram-treated mice. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic for treating Lyme disease. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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19 pages, 983 KiB  
Article
NSAIDs as a Drug Repurposing Strategy for Biofilm Control
by Cláudia Leão, Anabela Borges and Manuel Simões
Antibiotics 2020, 9(9), 591; https://doi.org/10.3390/antibiotics9090591 - 10 Sep 2020
Cited by 40 | Viewed by 5421
Abstract
Persistent infections, usually associated with biofilm-producing bacteria, are challenging for both medical and scientific communities. The potential interest in drug repurposing for biofilm control is growing due to both disinvestment in antibiotic R&D and reduced efficacy of the available panel of antibiotics. In [...] Read more.
Persistent infections, usually associated with biofilm-producing bacteria, are challenging for both medical and scientific communities. The potential interest in drug repurposing for biofilm control is growing due to both disinvestment in antibiotic R&D and reduced efficacy of the available panel of antibiotics. In the present study, the antibacterial and antibiofilm activities of four non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam (PXC), diclofenac sodium (DCF), acetylsalicylic acid (ASA) and naproxen sodium (NPX) were evaluated against Escherichia coli and Staphylococcus aureus. The minimum inhibitory/bactericidal concentrations (MICs and MBCs) and the dose–response curves from exposure to the selected NSAIDs were determined. MICs were found for PXC (800 μg/mL) and ASA (1750 μg/mL) against E. coli, and for DCF (2000 μg/mL) and ASA (2000 μg/mL) against S. aureus. No MBCs were found (>2000 μg/mL). The potential of NSAIDs to eradicate preformed biofilms was characterized in terms of biofilm mass, metabolic activity and cell culturability. Additionally, the NSAIDs were tested in combination with kanamycin (KAN) and tetracycline (TET). ASA, DCF and PXC promoted significant reductions in metabolic activity and culturability. However, only PXC promoted biofilm mass removal. Additive interactions were obtained for most of the combinations between NSAIDs and KAN or TET. In general, NSAIDs appear to be a promising strategy to control biofilms as they demonstrated to be more effective than conventional antibiotics. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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12 pages, 2254 KiB  
Article
Characterization of Five Novel Anti-MRSA Compounds Identified Using a Whole-Animal Caenorhabditis elegans/Galleria mellonella Sequential-Screening Approach
by Rajamohammed Khader, Nagendran Tharmalingam, Biswajit Mishra, LewisOscar Felix, Frederick M. Ausubel, Michael J. Kelso and Eleftherios Mylonakis
Antibiotics 2020, 9(8), 449; https://doi.org/10.3390/antibiotics9080449 - 27 Jul 2020
Cited by 9 | Viewed by 3536
Abstract
There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then [...] Read more.
There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then evaluated in the wax moth caterpillar Galleria mellonella infection model to confirm efficacy and low toxicity at a whole animal level. This multi-host approach is a powerful tool for revealing compounds that show antibacterial effects and relatively low toxicity at the whole organism level. This paper reports the use of the multi-host approach to identify and validate five new anti-staphylococcal compounds: (1) 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol(PPT), (2) (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl cyclopropanecarboxylate dihydrochloride(NNC), (3) 4,5,6,7-tetrabromobenzotriazole (TBB), (4) 3-[2-[2-chloro-4-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl] benzoic acid(GW4064), and (5) N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)amino] benzamide(PD198306). The compounds reduced the severity of methicillin-resistant Staphylococcus aureus (MRSA, strain MW2) infections in both C. elegans and G. mellonella and showed minimal inhibitory concentrations (MICs) in the range of 2–8 µg/mL. Compounds NNC, PPT, and TBB permeabilized MRSA-MW2 cells to SYTOX green, suggesting that they target bacterial membranes. Compound TBB showed synergistic activity with doxycycline and oxacillin against MRSA-MW2, and compounds PPT, NNC, GW4064, and PD198306 synergized with doxycycline, polymyxin-B, gentamicin, and erythromycin, respectively. The study demonstrates the utility of the multi-host approach with follow-up hit characterization for prioritizing anti-MRSA compounds for further evaluation. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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10 pages, 623 KiB  
Article
Antibacterial Activity of Colloidal Silver against Gram-Negative and Gram-Positive Bacteria
by Andrea Vila Domínguez, Rafael Ayerbe Algaba, Andrea Miró Canturri, Ángel Rodríguez Villodres and Younes Smani
Antibiotics 2020, 9(1), 36; https://doi.org/10.3390/antibiotics9010036 - 19 Jan 2020
Cited by 65 | Viewed by 20308
Abstract
Due to the emergence of antimicrobial resistance, new alternative therapies are needed. Silver was used to treat bacterial infections since antiquity due to its known antimicrobial properties. Here, we aimed to evaluate the in vitro activity of colloidal silver (CS) against multidrug-resistant (MDR) [...] Read more.
Due to the emergence of antimicrobial resistance, new alternative therapies are needed. Silver was used to treat bacterial infections since antiquity due to its known antimicrobial properties. Here, we aimed to evaluate the in vitro activity of colloidal silver (CS) against multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria. A total of 270 strains (Acinetobacter baumannii (n = 45), Pseudomonas aeruginosa (n = 25), Escherichia coli (n = 79), Klebsiella pneumoniae (n = 58)], Staphylococcus aureus (n = 34), Staphylococcus epidermidis (n = 14), and Enterococcus species (n = 15)) were used. The minimal inhibitory concentration (MIC) of CS was determined for all strains by using microdilution assay, and time–kill curve assays of representative reference and MDR strains of these bacteria were performed. Membrane permeation and bacterial reactive oxygen species (ROS) production were determined in presence of CS. CS MIC90 was 4–8 mg/L for all strains. CS was bactericidal, during 24 h, at 1× and 2× MIC against Gram-negative bacteria, and at 2× MIC against Gram-positive bacteria, and it did not affect their membrane permeabilization. Furthermore, we found that CS significantly increased the ROS production in Gram-negative with respect to Gram-positive bacteria at 24 h of incubation. Altogether, these results suggest that CS could be an effective treatment for infections caused by MDR Gram-negative and Gram-positive bacteria. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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Review

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12 pages, 582 KiB  
Review
Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing
by Álvaro Mourenza, José A. Gil, Luis M. Mateos and Michal Letek
Antibiotics 2020, 9(9), 550; https://doi.org/10.3390/antibiotics9090550 - 28 Aug 2020
Cited by 22 | Viewed by 7929
Abstract
Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen Mycobacterium tuberculosis and produces 1.5 million deaths every year. The incidence of tuberculosis has decreased during the last decade, but the [...] Read more.
Tuberculosis is the leading cause of death, worldwide, due to a bacterial pathogen. This respiratory disease is caused by the intracellular pathogen Mycobacterium tuberculosis and produces 1.5 million deaths every year. The incidence of tuberculosis has decreased during the last decade, but the emergence of MultiDrug-Resistant (MDR-TB) and Extensively Drug-Resistant (XDR-TB) strains of M. tuberculosis is generating a new health alarm. Therefore, the development of novel therapies based on repurposed drugs against MDR-TB and XDR-TB have recently gathered significant interest. Recent evidence, focused on the role of host molecular factors on M. tuberculosis intracellular survival, allowed the identification of new host-directed therapies. Interestingly, the mechanism of action of many of these therapies is linked to the activation of autophagy (e.g., nitazoxanide or imatinib) and other well-known molecular pathways such as apoptosis (e.g., cisplatin and calycopterin). Here, we review the latest developments on the identification of novel antimicrobials against tuberculosis (including avermectins, eltrombopag, or fluvastatin), new host-targeting therapies (e.g., corticoids, fosfamatinib or carfilzomib) and the host molecular factors required for a mycobacterial infection that could be promising targets for future drug development. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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20 pages, 763 KiB  
Review
Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases
by Olga Pacios, Lucia Blasco, Inès Bleriot, Laura Fernandez-Garcia, Mónica González Bardanca, Antón Ambroa, María López, German Bou and Maria Tomás
Antibiotics 2020, 9(2), 65; https://doi.org/10.3390/antibiotics9020065 - 6 Feb 2020
Cited by 123 | Viewed by 17258
Abstract
Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections [...] Read more.
Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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Other

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29 pages, 1332 KiB  
Perspective
Antifungal Drug Repurposing
by Jong H. Kim, Luisa W. Cheng, Kathleen L. Chan, Christina C. Tam, Noreen Mahoney, Mendel Friedman, Mikhail Martchenko Shilman and Kirkwood M. Land
Antibiotics 2020, 9(11), 812; https://doi.org/10.3390/antibiotics9110812 - 15 Nov 2020
Cited by 38 | Viewed by 7784
Abstract
Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences [...] Read more.
Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as Aspergillus fumigatus having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene promoter region and a leucine-to-histidine substitution at codon 98 of CYP51A. Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control. Full article
(This article belongs to the Special Issue Drugs Repurposing for the Treatment of Bacterial Infections)
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