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

Numerous species are responsible for fungal infections; however, 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 strains. A previous study by our group demonstrated that batzelladine D can inhibit the Pdr5p transporter in . In the present study, our aim was to investigate the efficacy of batzelladine D in inhibiting the main efflux pumps of , CaCdr1p and CaCdr2p, as well as to evaluate the effect of the compound on biofilm. Assays were conducted using a clinical isolate of expressing both transporters. Additionally, to allow the study of each transporter, 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 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 infections can be suggested.