Batzelladine D, a Marine Natural Product, Reverses the Fluconazole Resistance Phenotype Mediated by Transmembrane Transporters in Candida albicans and Interferes with Its Biofilm: An In Vitro and In Silico Study

Numerous <i>Candida</i> species are responsible for fungal infections; however, <i>Candida albicans</i> stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and/or biofilm formation, mechanisms of resistance commonly found in <i>C. albicans</i> strains. A previous study by our group demonstrated that batzelladine D can inhibit the Pdr5p transporter in <i>Saccharomyces cerevisiae</i>. In the present study, our aim was to investigate the efficacy of batzelladine D in inhibiting the main efflux pumps of <i>Candida albicans</i>, CaCdr1p and CaCdr2p, as well as to evaluate the effect of the compound on <i>C. albicans</i> biofilm. Assays were conducted using a clinical isolate of <i>Candida albicans</i> expressing both transporters. Additionally, to allow the study of each transporter, <i>S. cerevisiae</i> mutant strains overexpressing CaCdr1p or CaCdr2p were used. Batzelladine D was able to reverse the fluconazole resistance phenotype by acting on both transporters. The compound synergistically improved the effect of fluconazole against the clinical isolate when tested in the <i>Caenorhabditis elegans</i> animal model. Moreover, the compound disrupted the preformed biofilm. Based on the obtained data, the continuation of batzelladine D studies as a potential new antifungal agent and/or chemosensitizer in <i>Candida albicans</i> infections can be suggested.