TAC1b mutation in Candida auris decreases manogepix susceptibility owing to increased CDR1 expression

• Published in: Antimicrobial agents and chemotherapy 2024-12, p.e0150824
• Main Authors: Hirayama, Tatsuro, Miyazaki, Taiga, Tanaka, Rina, Kitahori, Natsume, Yoshida, Masataka, Takeda, Kazuaki, Ide, Shotaro, Iwanaga, Naoki, Tashiro, Masato, Takazono, Takahiro, Izumikawa, Koichi, Yanagihara, Katsunori, Makimura, Koichi, Tsukamoto, Kazuhiro, Mukae, Hiroshi
• Format: Article
• Language: English
• Subjects: Mechanisms of Resistance; Mycology
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.01508-24

is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of species to manogepix have been reported previously, those of are yet to be studied. To investigate the resistance mechanisms of , we exposed a clinical isolate (clade I) to manogepix and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in . We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high expression. Moreover, we generated a strain deficient in and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the mutation in upregulates expression and decreases its susceptibility to manogepix.