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

Kirsten Nielsen,David R. Boulware,J. Marina Yoder,Elliot S. Gerlach,Tony S. Luggya,Sophie Altamirano,David B. Meya,Joshua Rhein,Andrew Akampurira

doi:10.3389/fcimb.2021.695240

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.

Highlights

Cryptococcus neoformans is an environmentally acquired pathogenic yeast that causes the disease cryptococcal meningitis
The in vitro EUCAST broth microdilution assay IC50 measurements for C. neoformans clinical isolates showed no correlation between high fluconazole IC50 and activity of the experimental antifungal drug ATI-2307 or amphotericin B
While we only analyzed strains from Uganda and differences in fluconazole resistance are observed in populations from across the globe, given the completely different mode of action of ATI-2307 it is likely that our results showing no association between ATI-2301 and fluconazole resistance will be representative for C. neoformans

Summary

Introduction

Cryptococcus neoformans is an environmentally acquired pathogenic yeast that causes the disease cryptococcal meningitis. The small repertoire of antifungal drugs remains a critical limitation. The location of the ATI-2307 Activity Versus Fluconazole IC50 infection in the central nervous system, where the blood-brain barrier complicates or limits drug dissemination, further reduces the antifungal drugs that can be used successfully for cryptococcal meningitis therapy (Felton et al, 2014; Roemer and Krysan, 2014). Because many cryptococcal meningitis patients are immunocompromised and often receiving other drug treatments, drug-drug interactions must be considered (Vadlapatla et al, 2014). The most effective antifungal drug for treatment of cryptococcal meningitis, amphotericin B, is known for its potential to cause significant side effects and need for intravenous administration (Klepser, 2011)

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