Oteseconazole

Oteseconazole is an azole metalloenzyme inhibitor that targets CYP51 (also known as 14α demethylase), an enzyme that demethylates the 14-α position of lanosterol to form ergosterol. In yeast and fungi, the formation of ergosterol plays an important role in the integrity, permeability and fluidity of cell membranes. Therefore, because of its ability to bind and inhibit CYP51, oteseconazole is active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC). Besides blocking the formation of ergosterol, oteseconazole also promotes the accumulation of 14-methylated sterols that lead to fungal cell death. To limit off-target toxicity, oteseconazole has a tetrazole metal-binding group that gives it a lower affinity for the human CYP51 isoenzyme.

Mechanisms of drug resistance were evaluated in vitro, and increases in oteseconazole minimum inhibitory concentrations were associated with the upregulation of efflux pumps CDR1 and MDR1, and the azole target itself (CYP51). Oteseconazole had in vitro activity against Candida spp. that were resistant to fluconazole, and it was active against most of the microorganisms associated with RVVC: Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida lusitaniae and Candida dubliniensis. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.