Comprehensive Insights into Sugar Transporters of Candidozyma auris and Their Roles in Antifungal Resistance

TL;DR

This study explores how sugar transporters in Candidozyma auris may contribute to antifungal resistance by affecting drug import and membrane permeability.

Contribution

The study identifies Hgt13p as a key sugar transporter involved in fluconazole import and resistance in Candidozyma auris.

Findings

C. auris HGTs are more closely related to C. albicans than S. cerevisiae.

The Δhgt13 strain shows increased fluconazole resistance and reduced intracellular drug accumulation.

Molecular simulations confirm strong interactions between fluconazole and Hgt13p.

Abstract

In Candida species, including Candidozyma auris (formerly Candida auris), overexpression of efflux pumps is a well-established mechanism of antifungal resistance. However, accumulating evidence indicates that impaired drug import may also significantly contribute to reduced antifungal susceptibility. Sugar importers, historically viewed solely as hexose transporters (HGTs), are now emerging as potential indirect modulators of antifungal uptake. Here, we performed a comprehensive inventory and functional analysis of the HGT family in C. auris to assess its contribution to antifungal import. Phylogenetic analyses revealed that C. auris HGTs are more closely related to those of Candida albicans (C. albicans) than Saccharomyces cerevisiae (S. cerevisiae). All HGT genes showed basal expression, with several significantly downregulated upon fluconazole (FLC) exposure. To establish functional relevance, we generated a mini-library of HGT deletion mutants. Notably, the Δhgt13 strain exhibited markedly increased FLC resistance, concomitant with reduced intracellular FLC accumulation and decreased membrane permeability. Consistently, molecular docking and molecular dynamics simulations demonstrated strong and stable interactions between FLC and Hgt13p. Together, these findings implicate Hgt13p as a key determinant of FLC import and membrane permeability, revealing reduced FLC import could also contribute to antifungal resistance in C. auris.

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