Oteseconazole is a novel tetrazole that has activity against bacteria causing vulvovaginal candidiasis (RVVC). It is a selective inhibitor of fungal cytochrome P450 enzyme 51 (CYP51). The tetrazole group of Oteseconazole increases its selectivity for fungal CYP51 and reduces off-target interactions with CYP51. Human CYP51 is a cytochrome P450 enzyme in the endoplasmic reticulum that is essential for cholesterol biosynthesis by removing a methyl group from lanosterol. Microbial CYP51 enzymes are targets for antifungals but human CYP51 is relatively resistant to these antifungals.
| Mechanism of Action |
Oteseconazole is a selective inhibitor of fungal lanosterol 14α-demethylase (CYP51). CYP51 plays role in maintaining the integrity and growth of fungal cell membranes. If this enzyme is inhibited, Through inhibition of these enzymes, ergosterol cannot be synthesized. Ergosterol is a key component of fungal cell membrane development. This disruption leads to fungal membrane permeability, leading to death of fungal cells. The tetrazole metal-binding group of oteseconazole increases its selectivity for fungal CYP51 and reduces off-target interactions with human cytochrome P450s. |
| Spectrum | Oteseconazole has in vitro activity against Candida species and in vitro activity against the protozoan pathogen Trypanosoma cruzi. |
| Microbiology Applications |
In vitro resistance mechanisms for Oteseconazole were evaluated. Increases in MICs were associated with the upregulation of efflux pumps CDR1 and MDR1, and the azole target itself (CYP51). It had in vitro activity against Candida species that were resistant to fluconazole, and it was active against most of the microorganisms associated with vulvovaginal candidiasis including the following Candida species: albicans, glabrata, krusei, parapsilosis, tropicalis, lusitaniae and dubliniensis. Oteseconazole is a potent inhibitor of lanosterol 14α-demethylase activity of Candida albicans CYP51 with an IC50 of 0.01 nM in cell-free assays using radiolabeled [¹⁴C]lanosterol as a substrate. This inhibition was >10,000-fold selective over human CYP51, which showed no measurable binding at concentrations up to 1 μM. In summary, our present findings demonstrate the potency of Oteseconazole against Trypanosoma cruzi CYP51 enzyme and phenotypic efficacy against T. cruzi infection during in vitro and in vivo biological assays. T. cruzi is the causative agent of Chagas disease. |
| Molecular Formula | C23H16F7N5O2 |
| References |
Hoekstra WJ (2015) Clinical candidate VT-1161's antiparasitic effect in vitro, activity in a murine model of chagas disease, and structural characterization in complex with the target enzyme CYP51 from Trypanosoma cruzi. Antimicrob. Agents Chemother. 60(2):1058-1066 PMID 26643331 Warrilow AG et al (2014) The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob. Agents Chemother. 58(12):7121-7127 PMID 25224009 |