VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

10 Hope on the Horizon: HIV Protease Inhibitor, Atazanavir Overcomes Azole Resistance in Candida Auris Infection

Yehia Elgammal a ; Ehab A. Salama a ; Mohamed N. Seleem a# Corresponding author: abdallahyt@vt.edu

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

by 30% and 20%, respectively. When evaluated in a mouse model of disseminated candidiasis, the combination of atazanavir/itraconazole, along with ritonavir that serves as a bioavailability booster, significantly reduced C. auris’ burden in murine kidneys, generating a 1.15-log 10 colony forming unit (CFU) (~93%) reduction. Altogether, the data indicate that atazanavir is a potent azole chemo-sensitizing agent that merits further investigation.

Candida auris represents an urgent public health threat that has been linked to numerous outbreaks around the world and is associated with a significantly high mortality rate. Therapeutic options are currently limited to 3 main classes of antifungals (azoles, polyenes, and echinocandins) to treat C. auris infections. The limited treatment options and the upsurge of drug resistance in C. auris , prompted us to evaluate a library of FDA-approved drugs for their ability to restore the anti- Candida activity of azole antifungal agents. We identified the HIV protease inhibitor atazanavir, as a co-drug that can overcome azole resistance in C. auris . Atazanavir

displayed a remarkable in vitro synergistic activity with itraconazole against 19/19 C. auris isolates with a fractional inhibitory concentration index (ΣFICI) that ranged from 0.09 to 0.38. Moreover, atazanavir restored the fungistatic activity of itraconazole against C. auris in an in vitro time-kill assay. Mechanistic studies revealed that atazanavir significantly interfered with C. auris efflux pumps which resulted in an increase in the Nile red fluorescence by ~50%. Additionally, atazanavir inhibited glucose transport and ATP synthesis, which caused the glucose utilization and ATP content in C. auris to decrease

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