VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

02 The Antifungal Agent, Miconazole Exhibits a Potent Antibacterial Activity Against Clostridioides Difficile

Ahmed A. Abouelkhair 1 , Nader S. Abutaleb 1 , Mohamed N. Seleem 1 Corresponding author: aabouelkhair@vt.edu

1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University

of 24 azoles against a diverse range of pathogenic C. difficile strains. Miconazole, econazole, and tioconazole displayed the most potent activity against C. difficile inhibiting the growth of 50% of tested isolates (MIC 50 ) at concentrations of 1 μg/ml, 2 μg/ml, and 2 μg/ml, respectively. Miconazole was selected for further investigation since it demonstrated the most potent anti- C. difficile activity, and it is orally bioavailable. In a time-kill kinetics study, miconazole showed a fast bactericidal activity outperforming vancomycin, where it decreased a high bacterial inoculum by more than 3 log 10 within 2-4 hours and completely cleared the bacterial burden after 4 hours. Physicochemical properties of miconazole including, the effects of pH, pre-exposure to simulated gastric fluid (SGF), and simulated intestinal fluid (SIF), were also examined. High pH values did not affect the

miconazole’s antibacterial action, and it retained the same potency after being exposed to SGF and SIF. Furthermore, miconazole did not show inhibitory activity against key species that compose the host intestinal microbiota and showed a prolonged post antibiotic effect (PAE) (>6 hours) exceeding that of the drug of choice, vancomycin. Overall, these results indicate that miconazole merits further investigation as a potent and selective anti-clostridial agent to replenish the dry pipeline of new anti- C. difficile therapeutics.

Clostridioides difficile is a prominent source of healthcare-associated infections and is regarded as an urgent public health problem globally. The only FDA approved antibiotics for the treatment of C. difficile infection (CDI) are vancomycin and fidaxomicin. The high rate of treatment failure and recurrence linked to these antibiotics, as well as the rising number of infections, make CDI treatment extremely difficult. Therefore, it is imperative to find new, powerful anti- C. difficile drugs. When compared to de novo drug innovation, drug repurposing is a potential technique for reducing costs and time and decreasing risks associated with de novo drug discovery. Utilizing this approach, we screened 3200 FDA-approved drugs against C. difficile , and the results showed that miconazole is a powerful inhibitor of the bacterium with a minimum inhibitory concentration (MIC) of 1 μg/ml. On the strength of this, we tested a library

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