Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo
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....
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.05031-22 |
| _version_ | 1797741777394860032 |
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| author | Grace Kaul Abdul Akhir Manjulika Shukla Hasham Shafi Ravikumar Akunuri Gaurav Pawar Mahammad Ghouse Nanduri Srinivas Sidharth Chopra |
| author_facet | Grace Kaul Abdul Akhir Manjulika Shukla Hasham Shafi Ravikumar Akunuri Gaurav Pawar Mahammad Ghouse Nanduri Srinivas Sidharth Chopra |
| author_sort | Grace Kaul |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T14:31:35Z |
| format | Article |
| id | doaj.art-99fea40cfddf47b598bf381f73caa6b2 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-12T14:31:35Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-99fea40cfddf47b598bf381f73caa6b22023-08-17T13:04:13ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-08-0111410.1128/spectrum.05031-22Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In VivoGrace Kaul0Abdul Akhir1Manjulika Shukla2Hasham Shafi3Ravikumar Akunuri4Gaurav Pawar5Mahammad Ghouse6Nanduri Srinivas7Sidharth Chopra8Division of Molecular Microbiology and Immunology, Lucknow, Uttar Pradesh, IndiaDivision of Molecular Microbiology and Immunology, Lucknow, Uttar Pradesh, IndiaDivision of Molecular Microbiology and Immunology, Lucknow, Uttar Pradesh, IndiaDivision of Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, IndiaDepartment of Chemical Sciences, NIPER Hyderabad, Hyderabad, Telengana, IndiaDepartment of Chemical Sciences, NIPER Hyderabad, Hyderabad, Telengana, IndiaDepartment of Chemical Sciences, NIPER Hyderabad, Hyderabad, Telengana, IndiaDepartment of Chemical Sciences, NIPER Hyderabad, Hyderabad, Telengana, IndiaDivision of Molecular Microbiology and Immunology, Lucknow, Uttar Pradesh, IndiaABSTRACT 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.https://journals.asm.org/doi/10.1128/spectrum.05031-22oxiconazoleStaphylococcus aureusdrug resistancedrug repurposingmultidrug resistance |
| spellingShingle | Grace Kaul Abdul Akhir Manjulika Shukla Hasham Shafi Ravikumar Akunuri Gaurav Pawar Mahammad Ghouse Nanduri Srinivas Sidharth Chopra Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo Microbiology Spectrum oxiconazole Staphylococcus aureus drug resistance drug repurposing multidrug resistance |
| title | Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo |
| title_full | Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo |
| title_fullStr | Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo |
| title_full_unstemmed | Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo |
| title_short | Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo |
| title_sort | oxiconazole potentiates gentamicin against gentamicin resistant staphylococcus aureus in vitro and in vivo |
| topic | oxiconazole Staphylococcus aureus drug resistance drug repurposing multidrug resistance |
| url | https://journals.asm.org/doi/10.1128/spectrum.05031-22 |
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