Flavonoids as a Potential Antifungal Alternative Against Candida auris (Candidozyma auris) from Clades III and IV

<i>Candida auris</i> is a critical emerging pathogen of high priority due to its ability to develop multidrug resistance to various antifungals. Given the increase in cases associated with <i>C. auris</i>, it is essential to evaluate new candidates with antifungal potential. In this context, flavonoids represent a promising source for the development of new therapeutic alternatives. In this study eleven flavonoids were evaluated for their antifungal activity against <i>C. auris</i> strains from clades III and IV. The flavonoids showed dose-dependent inhibition of <i>C. auris</i> growth. Toxicity tests were conducted using the in vivo <i>Tenebrio molitor</i> model. The flavonoids exhibited toxicity levels either comparable to or lower than reference antifungals. Also, the study examined the ability of the flavonoids to inhibit efflux pumps. Some of the flavonoids (quercetin, fisetin, hesperetin, luteolin and apigenin) reduced efflux pump activity, which is an important feature since these pumps actively expel antifungal drugs from the cell, reducing the drug's effectiveness. This suggests that the flavonoids might inhibit efflux pump activity, potentially enhancing the efficacy of antifungal treatments. The study supports the potential of flavonoids as new therapeutic agents for <i>C. auris</i>. Since they target efflux pumps, which are a significant mechanism of resistance in <i>C. auris</i>, flavonoids could be used either alone or in combination with existing antifungals to improve treatment outcomes.