VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

08 A Novel Combination of Amphotericin B and Lansoprazole to Combat the Fungal Superbug Candida Auris , Targeting the Mitochondrial Cytochrome BC1 Complex

Ehab A. Salama 1 ; Yehia Elgammal 1 ; Aruna Wijeratne 2 ; Mohamed N. Seleem 1 Corresponding author: ehabsalama@vt.edu

1 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech 2 Department of Biochemistry and Molecular Biology, Indiana, University School of Medicine, Indianapolis, IN

for the activity of amphotericin B. Lansoprazole exhibited potent synergistic interactions with the amphotericin B against 18/20 (90%) C. auris isolates. Proteome Integral Solubility Alteration (PISA) assay revealed that lansoprazole inhibits an essential target in the yeast cytochrome system (Rieske protein of the mitochondrial cytochrome bc1 complex) leading to increase in the oxidative stress in the fungal cells which consequently augment the oxidative damaging effect of amphotericin B on C. auris cells. The target was confirmed with the rotenone rescue assay. Most

Candida auris , has emerged as a problematic fungal pathogen usually associated with high morbidities and mortalities. Amphotericin B (AMB) is the most effective and broad-spectrum antifungal agent. However, the clinical efficacy of this drug has markedly affected with the emergence of C. auris which possessed extraordinary resistant profile against all available antifungal drugs including amphotericin B. In this study, by screening ~3,400 FDA-approved drugs we identified the proton pump inhibitor, lansoprazole (LNP) as a potent enhancer

importantly, lansoprazole restored the in vivo efficacy of amphotericin B in an immunocompromised mouse model, resulting in a 1.7-log (~98%) CFU reduction in the kidney burden of C. auris. Our results identified lansoprazole as a potent enhancer to the antifungal activity of amphotericin B in addition to identification of mitochondrial cytochrome bc1 as a novel drug target.

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