Mutations in transcription factors that confer fluconazole resistance also confer reduced susceptibility to manogepix in Candida auris (Candidozyma auris), Candida albicans, Candida parapsilosis, and Candida glabrata (Nakaseomyces glabratus).

Abstract

The fungal pathogen Candida auris is of global concern due to high levels of multidrug resistance and its propensity to cause infectious outbreaks. Over 90% of isolates are resistant to fluconazole, the most commonly prescribed antifungal worldwide. Fluconazole resistance is multifactorial with many isolates carrying mutations in the gene encoding the transcriptional regulator Tac1B, leading to increased expression of the gene encoding the ATP-binding cassette (ABC) transporter Cdr1. Recently, a study in C. auris examining mechanisms of in vitro-evolved reduced susceptibility to manogepix, a promising antifungal agent currently in clinical trials, found a TAC1B mutation that confers reduced manogepix and fluconazole susceptibility. We hypothesized that mutations in C. auris TAC1B and similar transcription factors in other Candida species that confer fluconazole resistance might also confer reduced susceptibility to manogepix. We measured manogepix susceptibilities for selected isolates and strains and found that mutations in C. auris TAC1B, C. albicans and C. parapsilosis TAC1, and C. glabrata PDR1 confer reduced manogepix susceptibility in a manner dependent on ABC transporters, such as Cdr1. Our findings raise the possibility of fluconazole and manogepix cross-resistance for clinical isolates harboring mutations in these genes.