ATI-2307 Exhibits Equivalent Antifungal Activity in Cryptococcus neoformans Clinical Isolates With High and Low Fluconazole IC50

Abstract

Half maximal inhibitory concentrations (IC₅₀) to the experimental drug ATI-2307 and complete inhibition (IC₉₀) of the common clinically used antifungal drug amphotericin B were determined by microbroth dilution assay for a collection of 69 clinical isolates of Cryptococcus neoformans from Uganda that had high fluconazole IC₅₀ values. The majority of the clinical isolates tested had fluconazole IC₅₀ at or above 8 µg/mL, but were susceptible to both amphotericin B (IC₉₀ ≤1 μg/mL) and ATI-2307 (IC50 ≤0.0312 µg/mL). No correlation between increased fluconazole minimum inhibitory concentration (MIC) and ATI-2307 or amphotericin B MIC was observed, suggesting that the cellular changes impacting fluconazole susceptibility did not impact the effectiveness of ATI-2307. Our results suggest that ATI-2307 is a promising new antifungal drug for use in the context of high fluconazole or other antifungal drug MICs and/or in combination drug therapy regimens.

Keywords: ATI-2307; Cryptococcus; IC50; T-2307; antifungal; azole; resistance; susceptibility.