Repurposing HIV Protease Inhibitors as Antifungal Chemosensitizers Against Multidrug Resistant Candida auris: Promise, Limitations, and Translational Challenges

Candidozyma auris (formerly known as Candida auris hereafter , C. auris ) is an emerging healthcare associated fungal pathogen. Which is associated with multidrug resistance, environmental persistence, and invasive infections in vulnerable patients. Reduced proneness to established antifungal agents has induced investigation of unorthodox strategies. One approach is antifungal chemosensitization, in which a compound with restricted or no direct antifungal activity enhances the effect of a prevailing antifungal. Preclinical studies have investigated chosen human immunodeficiency virus (HIV) protease inhibitors, including lopinavir, ritonavir, atazanavir, and saquinavir, in cooperation with azoles or amphotericin B against C. auris . Reported findings include in vitro synergy, enhanced fungal killing, and reduced fungal burden in experimental infection models. Intended clarifications include altered drug efflux and changes or modifications in cellular physiology, but the underlying/fundamental mechanisms remain incompletely established. Significantly, limitations include combination and isolate dependent effects, use of selected strains in some infection models, incomplete pharmacokinetic and toxicity data, and no demonstrated clinical efficacy. This Perspective evaluates the evidence and determines the independent validation, exposure response studies, drug interaction assessments, and safety studies needed before clinical application can be considered.