Mutations in transcription factors that confer fluconazole resistance also confer reduced susceptibility to manogepix in (), , , and ().

The fungal pathogen 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 examining mechanisms of -evolved reduced susceptibility to manogepix, a promising antifungal agent currently in clinical trials, found a mutation that confers reduced manogepix and fluconazole susceptibility. We hypothesized that mutations in and similar transcription factors in other 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 , and , and 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.