A screen to identify antifungal antagonists reveals a variety of pharmacotherapies that induce echinocandin tolerance in <i>Candida albicans</i>

Through screening a comprehensive collection of drugs approved for human use, we identified over 20 that oppose the antifungal activity of the echinocandins upon the infectious yeast, <i>Candida albicans</i>. More detailed evaluation of five such drugs, including the atypical antipsychotic aripiprazole and the tyrosine kinase inhibitor ponatinib, indicated they promote <i>C. albicans</i> survival following exposure to the echinocandin antifungals. The activity of the five selected antagonists was dependent upon the Mkc1p mitogen-activated protein kinase pathway; however, ponatinib was paradoxically shown to suppress phosphorylation and therefore activation of Mkc1p itself. Components of several other signaling pathways are also required, including those of calcineurin and casein kinase-2, suggesting the observed antagonism required much of the cell wall stress responses previously described for <i>C. albicans</i>. Transcriptome analysis revealed that the antagonists stimulated the expression of genes involved in xenobiotic and antifungal resistance and suppressed the expression of genes associated with hyphal growth. Thus, the echinocandin antagonistic drugs modulate <i>C. albicans</i> physiology in ways that could impact its pathogenicity and/or response to therapeutic intervention. Finally, a mutant lacking the Efg1p transcription factor, which has a central role in the activation of <i>C. albicans</i> hyphal growth, was found to have intrinsically high levels of echinocandin tolerance, suggesting a link between modulation of morphogenesis-related signaling and echinocandin tolerance.