A targeted drug-repurposing strategy identifies Tavaborole (Kerydin) as a potent fungistatic agent against Candida auris

Abstract

Candidozyma auris (Candida auris) is an emerging multidrug-resistant fungal pathogen posing a major global health threat. In this study, we employed a targeted drug-repurposing strategy to identify novel indications for existing FDA-approved compounds against C. auris, leading to the identification of Tavaborole as a potent fungistatic agent. Tavaborole displayed robust activity across all five tested clades of C. auris, as well as against Candida albicans and Candida glabrata. To investigate drug resistance mechanisms of C. auris, we applied quantitative proteomics analyses following exposure to Tavaborole and Amphotericin B (AmB), complemented by electron microscopy. Proteomic profiling revealed that C. auris mounts distinct but overlapping adaptive responses to antifungal stress, involving stress response pathways, metabolic reprogramming and amino acid biosynthesis. While Tavaborole primarily induced targeted stress adaptation, AmB triggered a broader, multi-pronged resistance response including oxidative stress mitigation, osmolyte production and metabolic remodeling. Shared alterations in glycogen metabolism and amino acid biosynthesis suggest conserved antifungal adaptation mechanisms. Altogether, this study highlights Tavaborole as a promising antifungal candidate against C. auris, sheds novel insights into drug resistance mechanisms employed the pathogen and delivers a drug-repurposing procedure highly customizable to target other microorganisms. ImportanceCandida auris is an emerging multidrug-resistant fungal pathogen responsible for healthcare-associated infections representing a high-priority antimicrobial resistance (AMR) threat due to its limited treatment options, high transmissibility, and capacity to cause severe and often fatal outbreaks. The slow pace of antifungal drug development underscores the urgent need for alternative strategies to expand the antifungal arsenal against priority pathogens such as C. auris. In this study, we demonstrate that a targeted drug-repurposing approach can efficiently identify antifungal activity from a small, curated set of FDA-approved compounds, leading to the discovery of Tavaborole as a fungistatic agent with broad activity across multiple C. auris clades. By integrating a customizable drug screening procedure with quantitative proteomics and electron microscopy, this work provides insights into antifungal resistance mechanisms. This study highlights how rational drug-repurposing strategies can rapidly identify clinically relevant drug candidates to counter emerging pathogens and address antifungal resistance.