P092 Otilonium bromide is a potent antifungal agent against fluconazole- and flucytosine-resistant Cryptococcus neoformans strains

Abstract

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMObjectives Cryptococcus neoformans is a worldwide threat causing global pulmonary and systemic infections in humans. However, only three drugs are available for the treatment of cryptococcosis: fluconazole, amphotericin B, and flucytosine. Drug repurposing, the process of using a drug for an indication different from the initial indication, is an emerging approach in the discovery of new antifungal drugs. We've set out to identify repurposable drugs for cryptococossis.MethodsWe screened the United States FDA-approved drugs for antifungal activity against C. albicans lab strain SC5314. We tested the antifungal profile against major human fungal pathogens including C. neoformans. In order to uncover the mechanism of action against C. neoformans, lab strain H99 was used to evolve drug resistant adaptors. Next-generation sequencing technology was used to investigate the genome change of drug resistant adaptors. SNP calling was also performed to identify possible mutations causing drug resistance.ResultsHere we found that otilonium bromide (OTB), which is extensively used to treat patients affected by the irritable bowel syndrome, had broad-spectrum antifungal activity. OTB was active against fluconaozle-resistant and flucotysine-resistant C. neoformans strains. Furthermore, we found resistance to OTB was mostly due to duplication of chromosome 6. Further work will be on the identification of the Candidate gene on chromosome 6 which is required OTB resistance.ConclusionThis study highlights the potential application of OTB as a new antifungal drug against C. neoformans strains susceptible or resistant to commonly used antifungal drugs.