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Prior to characterization of antifungal inhibitors that target CYP51, Trichophyton rubrum CYP51 was expressed in Escherichia coli , purified, and characterized. T. rubrum CYP51 bound lanosterol, obtusifoliol, and eburicol with similar affinities (dissociation constant [ K d  ] values, 22.7, 20.3, and 20.9 μM, respectively) but displayed substrate specificity, insofar as only eburicol was demethylated in CYP51 reconstitution assays (turnover number, 1.55 min -1 ; K m  value, 2 μM). The investigational agent VT-1161 bound tightly to T. rubrum CYP51 ( K d  = 242 nM) with an affinity similar to that of clotrimazole, fluconazole, ketoconazole, and voriconazole ( K d  values, 179, 173, 312, and 304 nM, respectively) and with an affinity lower than that of itraconazole ( K d  = 53 nM). Determinations of 50% inhibitory concentrations (IC 50 s) using 0.5 μM CYP51 showed that VT-1161 was a tight-binding inhibitor of T. rubrum CYP51 activity, yielding an IC 50 of 0.14 μM, whereas itraconazole, fluconazole, and ketoconazole had IC 50 s of 0.26, 0.4, and 0.6 μM, respectively. When the activity of VT-1161 was tested against 34 clinical isolates, VT-1161 was a potent inhibitor of T. rubrum growth, with MIC 50 , MIC 90 , and geometric mean MIC values of ≤0.03, 0.06, and 0.033 μg ml -1 , respectively. With its selectivity versus human CYP51 and drug-metabolizing cytochrome P450s having already been established, VT-1161 should prove to be safe and effective in combating T. rubrum infections in patients.

The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through Its Inhibition of T. rubrum CYP51