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

ABSTRACT: The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2synergizes with caspofungin in vitro and in vivo without notable toxicity. 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

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Project description:Aspergillus species are a leading cause of invasive fungal infections. As resistance to first-line therapy involving triazole antifungal agents is rising, second-line therapy with echinocandins is expanding. Resistance to echinocandins is well-established to result from amino acid substitutions in the echinocandin drug target β-(1,3)-D-glucan synthase encoded by the fks1 gene. Recently, we identified several high MIC clinical isolates of A. fumigatus from patients failing echinocandin therapy that did not contain any mutation in the fks1 gene, indicating that echinocandin resistance in these isolates results from an undefined mechanism. To explore possible new mechanisms of resistance, we used a lab-derived strain, RG101, with a nearly identical susceptibility phenotype, as a model system. This strain does not contain fks1 mutations but showed prominent resistance to the echinocandin class drug caspofungin (CAS), while remaining sensitive to other echinocandins, azoles and polyenes. Glucan synthase isolated from RG101 was fully sensitive to drug. Yet, exposure to CAS during its growth yielded a modified enzyme that was insensitive (4-log orders) in kinetic inhibition assays to CAS, as well as other echinocandins. This induction of cross-resistance by CAS was also observed in clinical isolates. To determine the nature of a presumptive posttranslational modification (PTM) of the enzyme, we analyzed whole enzyme PTMs, including the known hot-spot regions, for methylation, acetylation and phosphorylation. While we did not identify any PTMs linked to resistance, analysis of the lipid microenvironment of CAS-induced resistant enzyme revealed a prominent increase in the abundance of dihydrosphingosine (DhSph) and phytosphingosine (PhSph). Exogenous addition of DhSph and PhSph to sensitive enzyme in in vitro kinetic inhibition assays recapitulated the CAS insensitivity of the cellular-derived enzyme. To further examine induction of drug-induced resistance, we used an in vitro assay to demonstrate that CAS, but not other echinocandin class drugs, prominently induced the production of mitochondrial-derived Reactive Oxygen Species (ROS) in A. fumigatus. RNASeq evaluation of whole cells confirmed a ROS signature in cells treated with CAS. Dampening the formation of ROS by antimycin A or thiourea eliminated the induction of drug resistance by CAS. We conclude that CAS-induced formation of ROS promotes a cellular stress response that alters the composition of plasma membrane lipids surrounding glucan synthase, changing its enzymatic properties to make it insensitive to echinocandins. This stress-induced response constitutes a novel mechanism of echinocandin resistance in Aspergillus, with implications for drug resistance and/or tolerance mechanisms in other fungal pathogens.

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

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