Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris

ABSTRACT: The frequent use of antifungal agents has contributed to the emergence of previously rare or unidentified drug-resistant fungal species, such as Candida auris, which presents mortality rates exceeding 40% and antifungal resistance rates surpassing 90%. The rise of life-threatening infections caused by these increasingly drug-resistant fungal pathogens, coupled with the limited arsenal of effective antifungal agents, necessitates the urgent development of novel strategies to combat multidrug resistance. In this study, we systematically evaluated the role of post-translational modifications (PTMs) of histone H3 in drug resistance in C. auris, focusing on acetylation mediated by the acetyltransferases Gcn5 and Rtt109, as well as methylation by the methyltransferases Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibited varying degrees of antifungal drug sensitivity. Notably, we discovered that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulate key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to major antifungal classes such as azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through modulation of the calcineurin signaling pathway and the transcription factor Cas5. In invasive infection models using Galleria mellonella and immunocompromised mice, the deletion of GCN5 significantly reduced the virulence of C. auris. Furthermore, we demonstrated that the Gcn5 inhibitor CPTH2, when combined with the antifungal drug caspofungin (CAS), exhibits a synergistic effect against C. auris in both in vitro and in vivo models without significant toxicity to human cells or mice. In conclusion, these findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.

ORGANISM(S): Candidozyma auris

PROVIDER: GSE293594 | GEO | 2025/04/05

REPOSITORIES: GEO