<i>TAC1b</i> mutation in <i>Candida auris</i> decreases manogepix susceptibility owing to increased <i>CDR1</i> expression

<i>Candida auris</i> 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 <i>Candida</i> species to manogepix have been reported previously, those of <i>C. auris</i> are yet to be studied. To investigate the resistance mechanisms of <i>C. auris</i>, we exposed a clinical isolate (clade I) to manogepix <i>in vitro</i> 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 <i>TAC1b</i>. 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 <i>CDR1</i> expression. Moreover, we generated a strain deficient in <i>CDR1</i> and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the <i>TAC1b</i> mutation in <i>C. auris</i> upregulates <i>CDR1</i> expression and decreases its susceptibility to manogepix.