In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans

Abstract

The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including Candida spp. To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 C. albicans clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs Յ0.15 g/ml) against predominantly fluconazole-resistant (Ն8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (Ͼ2 g/ml) to both tetrazoles compared to fluconazolesusceptible isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit of the assay for all triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R) but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole-and tetrazole-based sterol demethylase inhibitors.

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…The C. albicans strains used in this study carried multiple mechanisms of resistance. When comparing VT-1589 to VT-1161 in this study, VT-1598 had lower MIC 50 and MIC 90 values [36].…”

Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

“…VT-1598 has been effective in murine infection models with Candida, Coccidioides, and Cryptococcus species (23,37,38). However, reduced susceptibility has been observed to both VT-1161 and VT-1598 in clinical isolates of C. albicans, and this reduced in vitro susceptibility seems to be at least partly due to increased expression of the C. albicans ABC transporter Cdr1 (25,39). This parallels our results in C. glabrata, where Cdr1 and its regulator Pdr1 appear to play an important role in reduced susceptibility to both VT-1161 and VT-1598, more so than either Pdh1 or Snq2.…”

“…In particular, VT-1161 had previously shown to potently bind fungal CYP51 without binding the human equivalent of the fungal target enzyme, whereas VT-1598 boasts a broader spectrum of antifungal activity (20,22). Both agents have previously been shown to be effective against Candida strains, including azole-resistant strains, in vitro and in vivo (23)(24)(25)(26)(27).…”

Investigational Agents for the Treatment of Resistant Yeasts and Molds

“…1) [43-46, 47••, 48•]. It exhibited potent in vitro activity against most fluconazole-resistant C. albicans and C. krusei isolates (mean MIC ≤ 0.15 μg/mL) as well as echinocandin-resistant C. glabrata [44,49]. This effect was demonstrated in a mouse model of VVC which included fluconazole-resistant Candida species [50].…”