The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through its Inhibition of T. rubrum CYP51 [PublishAheadOfPrint]

Prior to characterization of antifungal inhibitors that target this enzyme, Trichophyton rubrum CYP51 was expressed in Escherichia coli, purified and characterized. T. rubrum CYP51 bound lanosterol, obtusifoliol and eburicol with similar affinities (K_d values 22.7, 20.3 and 20.9 μM), 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 similar affinity as clotrimazole, fluconazole, ketoconazole and voriconazole (K_d values 179, 173, 312, and 304 nM, respectively), and with lower affinity than itraconazole (K_d = 53 nM). IC₅₀ determinations using 0.5 μM CYP51 showed VT-1161 was a tight-binding inhibitor of T. rubrum CYP51 activity yielding an IC₅₀ value of 0.14 μM compared to 0.26, 0.4 and 0.6 μM for itraconazole, fluconazole and ketoconazole, respectively. When tested against 34 clinical isolates, VT-1161 was a potent inhibitor of T. rubrum growth with MIC₅₀, MIC₉₀, 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 CYPs having already been established, VT-1161 should prove safe and effective in combating T. rubrum infections in patients.

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