VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

09 Ritonavir, a Promising Cost-Effective Amphotericin Synergist Against Cryptococcal Meningitis Infection

Nour Alkashef; Mohamed Seleem Corresponding author: nouralkashef@vt.edu

Department of Biomedical Sciences and Pathobiology Virginia Polytechnic Institute and State University, Blacksburg

Cryptococcus neoformans causing life-threatening meningitis and represents an alarming global health threat associated with high mortality among immunocompromised individuals and HIV patients. The current arsenal of antifungal drugs to combat the growing problem of cryptococcus is very limited. Amphotericin B is the front line treatment for cryptococcal meningitis. However, the treatment with amphotericin B is commonly associated with severe adverse effects. In this study, we used the combinatorial approach to minimize the toxicity and to enhance the efficacy of amphotericin B against

C. neoformans. We evaluate the HIV-protease inhibitor, ritonavir, as a potential co-drug to work synergistically and to enhance the effectiveness of amphotericin B treatment. Ritonavir exhibits a potent in-vitro synergistic interactions when combined with amphotericin B against 100% (15/15) of the tested C. neoformans isolates with a fractional inhibitory concentration index (ΣFICI) ranging from 0.07 to 0.31. Notably, the combination of ritonavir with amphotericin B led to killing of all tested isolates within 3 hours as measured by time killing assays. As a part of the involved mechanistic study, ritonavir

significantly interferes with glucose transport in C. neoformans reducing its uptake by 52%. These data highlight the potential of antifungal combination between amphotericin B and ritonavir to combat C. neoformans infections. Furthermore, these data will provide insight into the potential clinical usefulness of ritonavir because it is commonly administered in HIV infected patients and cryptococcus is a leading cause of morbidity and mortality in those patients.

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