Abstract
Amid the mounting burden of multidrug-resistant (MDR) bacterial infections on health care worldwide, drug repurposing, a time and cost-effective strategy to identify new applications for drugs approved for other indications, can effectively fill the void in the current antibiotic pipeline. In this study, we have repurposed a topical antifungal agent, oxiconazole, in combination with gentamicin against skin infections caused by multidrug-resistant Staphylococcus aureus. Oxiconazole was identified as having antibacterial activity against S. aureus via whole-cell screening assays against clinically relevant bacterial pathogens. It exhibited a potent in vitro profile, including equipotent activity against clinical drug-susceptible and -resistant S. aureus and Enterococcus spp. Checkerboard assays and time-kill kinetics studies demonstrated its concentration-dependent killing and ability to synergize with the approved antibiotics daptomycin and gentamicin against susceptible and MDR S. aureus strains. Oxiconazole also significantly eradicated preformed S. aureus biofilms in vitro. Eventually, in an assessment of its ability to generate resistant S. aureus mutants via serial passaging, oxiconazole displayed an extremely low propensity for developing stable resistance in S. aureus. Its in vivo efficacy alone and in combination with synergistic antibiotics was assessed in a murine superficial skin infection model of S. aureus, where it strongly synergized with gentamicin, exhibiting superior activity to the untreated control and drug-alone treatment groups. Thus, oxiconazole can be repurposed as an antibacterial alone and in combination with gentamicin against susceptible and gentamicin-resistant S. aureus infections. IMPORTANCE Staphylococcus aureus, which causes the majority of nosocomial and community-acquired infections globally, is a WHO high-priority pathogen for antibiotic research and development. In addition to invasive infections, it is the causative agent of moderate to severe skin infections, with an increasing prevalence of infections caused by MDR strains such as methicillin-resistant S. aureus (MRSA). Our study highlights the repurposing of oxiconazole, a topical antifungal agent, as an ideal candidate for combination therapy with gentamicin against susceptible and drug-resistant S. aureus skin infections due to its extremely low propensity for resistance generation in S. aureus, activity against MDR strains, bactericidal killing kinetics alone and in combination, broad antifungal efficacy, and excellent safety and tolerability profile.