Abstract
Multidrug-resistant (MDR) Gram-negative bacteria are the top-priority pathogens to be eradicated. Drug repurposing (e.g., the use of non-antibiotics to treat bacterial infections) may be helpful to overcome the limitations of current antibiotics. Zidovudine (azidothymidine, AZT), a licensed oral antiviral agent, is a leading repurposed drug against MDR Gram-negative bacterial infections. However, the rapid emergence of bacterial resistance due to long-term exposure, overuse, or misuse limits its application, making it necessary to develop new alternatives. In this study, we investigated the efficacy of ciclopirox (CPX) as an alternative to AZT. The minimum inhibitory concentrations of AZT and CPX against MDR Gram-negative bacteria were determined; CPX appeared more active against β-lactamase-producing Escherichia coli, whereas AZT displayed no selectivity for any antibiotic-resistant strain. Motility assays revealed that β-lactamase-producing Escherichia coli strains were less motile in nature and more strongly affected by CPX than a parental strain. Resistance against CPX was not observed in E. coli even after 25 days of growth, whereas AZT resistance was observed in less than 2 days. Moreover, CPX effectively killed AZT-resistant strains with different resistance mechanisms. Our findings indicate that CPX may be utilized as an alternative or supplement to AZT-based medications to treat opportunistic Gram-negative bacterial infections.
Highlights
Academic Editor: Antonello Di PaoloThe emergence of multidrug-resistant (MDR) Gram-negative bacteria urgently require new strategies to treat infections caused by such bacteria
The results demonstrated that resistance to the control E. coli strain did not occur after 25 d of CPX exposure, whereas AZT treatment was associated with increased resistance in the same strain by more than 1000-fold within 2 d
The minimum inhibitory concentration (MIC) for bacterial strains was determined by the microbroth dilution method on 96-well plates as described in previous reports [30,43]
Summary
The emergence of multidrug-resistant (MDR) Gram-negative bacteria urgently require new strategies to treat infections caused by such bacteria. I.e., the identification of non-antibiotics for new therapeutic indications, is a promising alternative or adjuvant to treat MDR bacterial infections, obviating antibiotic-resistant biological pathways [1]. Many non-antibiotic drugs used as anticancer, antifungal, anthelmintic, and antiinflammatory agents possess antibacterial properties [2–4], and ~20 such drugs have been identified as candidates for drug repurposing or as adjuvants to antibiotics against MDR. Zidovudine ( known as azidothymidine, AZT), an antiviral drug used for human immuno-deficiency virus (HIV) treatment [7] and commercially available as Retrovir® , is regarded as a leading bactericidal drug or synergistic agent to antibiotics because it shows low minimum inhibitory concentration (MIC) values against MDR Gram-negative bacteria and increases the efficacy of amikacin, gentamicin, and last-resort antibiotics [8–15]. Despite its potential action as an antibacterial agent, drawbacks, including a high mutagenic potential [16], hematologic toxicity, and association with strong resistance development in
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