Activity of investigational tetrazole antifungals VT-1161 and VT-1598 against a collection of characterized fluconazole resistant Candida parapsilosis clinical isolates

Objectives:
To evaluate the activity of the tetrazole-based fungal CYP51 inhibitors VT-1611 and VT-1598 against a collection of characterized clinical Candida parapsilosis isolates with reduced susceptibility to triazoles.

Methods:
10 fluconazole-resistant clinical isolates of C. parapsilosis were included in this study. We have previously characterized this collection, which includes 3 isolates with ERG11 mutations encoding the Y132F amino acid substitution, 1 isolate which overexpresses ERG11 (12-fold), as well as 6 isolates observed to overexpress CDR1 (4- to 8-fold), and 3 isolates which overexpress MDR1 (25- to 51-fold). VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole minimum inhibitory concentrations (MIC) for each isolate were determined using CLSI methods in duplicate.

Results:
VT-1161 MIC (determined at 50% growth inhibition) ranged from 0.06 to 4mg/L (MIC50 0.06mg/L). VT-1598 MIC ranged from ≤0.015 to 0.125mg/L (MIC50 0.03mg/L). 3 isolates which overexpress CDR1 (4- to 5-fold) and 1 isolate which overexpresses MDR1 (25-fold), were observed to have VT-1161 and VT-1598 MIC of 0.06 and <0.015mg/L, respectively. All 3 isolates with ERG11 mutations encoding the Y132F amino acid substitution and concurrent CDR1 overexpression (5- to 8-fold) exhibited VT-1161 MIC of 2- 4mg/L, yet VT-1598 MIC remained substantially lower (0.03 to 0.06mg/L). The single isolate overexpressing ERG11 (12-fold) was observed to have an elevated VT-1598 MIC (0.125mg/L), but not an elevated VT-1161 MIC (0.06 mg/L). While all isolates were found to be resistant to fluconazole (MIC 8 to >64mg/L), only 6 isolates were non-susceptible to voriconazole (MIC 0.25 to 1mg/L). One isolate was observed to have an itraconazole MIC exceeding the previously reported epidemiologic cutoff value of 0.5mg/L. Posaconazole MIC were ≤0.125mg/L for all isolates tested.

Conclusion:
VT-1598 demonstrated potent activity against all isolates in this collection of C. parapsilosis clinical isolates with reduced susceptibility to triazoles. A wider range of VT-1161 susceptibility was observed, with the highest MIC (2 to 4mg/L) obtained for isolates that possess both an ERG11 mutation encoding the Y132F amino acid substitution and CDR1 overexpression. However, neither CDR1 or MDR1 overexpression alone were found to significantly increase VT-1161 or VT-1598 MIC in this collection of clinical isolates. Further investigation is needed to determine the direct impact of these and other yet to be identified sterol-demethylase inhibitor resistance mechanisms.

4 / Activity of investigational tetrazole antifungals VT-1161 and VT-1598 against a collection of characterized fluconazole resistant Candida parapsilosis clinical isolates