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

Abstract

VT-1161 and VT-1598 are promising investigational tetrazole antifungals that have shown in vitro and in vivo activity against Candida and other fungi. Candida glabrata is a problematic opportunistic pathogen that is associated with high mortality in invasive infection, as well as both intrinsic and rapidly acquired antifungal resistance. The MICs of VT-1161 and VT-1598 were determined by CLSI methodology to evaluate their in vitro activities against clinical C. glabrata isolates and strains containing individual deletions of the zinc cluster transcription factor genes PDR1 and UPC2A as well as the efflux transporter genes CDR1, PDH1, and SNQ2. Overall, both tetrazoles demonstrated relative activities comparable to those of the tested triazole antifungals against clinical C. glabrata isolates (MIC range, 0.25 to 2 mg/liter and 0.5 to 2 μg/ml for VT-1161 and VT-1598, respectively). Deletion of the PDR1 gene in fluconazole-resistant matched clinical isolate SM3 abolished the decreased susceptibility phenotype completely for both VT-1161 and VT-1598, similarly to the triazoles. UPC2A deletion also increased susceptibility to both triazoles and tetrazoles but to a lesser extent than PDR1 deletion. Of the three major transporter genes regulated by Pdr1, CDR1 deletion resulted in the largest MIC reductions for all agents tested, while PDH1 and SNQ2 deletion individually impacted MICs very little. Overall, both VT-1161 and VT-1598 have comparable activities to those of the available triazoles, and decreased susceptibility to these tetrazoles in C. glabrata is driven by many of the same known resistance mechanisms.

Antifungal Pipeline

“…This tetrazole demonstrates broad activity against most Candida species, dermatophytes, certain endemic fungi such as Coccidioides species, and selected Mucorales species. In Vitro studies suggest that the compound is active against fluconazole-resistant Candida strains such as Candida krusei and Candida glabrata , demonstrating activity similar to other triazoles such as voriconazole and posaconazole ( Schell et al., 2017b ; Nishimoto et al., 2019a ; Nishimoto et al., 2019b ).…”

Investigational Agents for the Treatment of Resistant Yeasts and Molds

“…delemar strains), Coccidioides species, B. dermatitis, and H. capsulatum (Fig. 1) [49,[96][97][98]. Like VT-1161, it is impacted by UPC2-and PDR1-mediated resistance mechanisms seen in triazole cross-resistant C. glabrata [97].…”

“…1) [49,[96][97][98]. Like VT-1161, it is impacted by UPC2-and PDR1-mediated resistance mechanisms seen in triazole cross-resistant C. glabrata [97]. Efficacy and safety were seen in mouse models studying VT-1598 for invasive C. auris infections, cryptococcal meningitis, and CNS coccidioidomycosis [98][99][100].…”

Antifungal Resistance among Less Prevalent Candida Non-albicans and Other Yeasts versus Established and under Development Agents: A Literature Review

“…For the triazoles, the NWT isolates were reported as having modifications of either the ABC or MFS transporters, or CDR gene overexpression, or individual deletions of the zinc cluster transcription factor genes PDR1 and UPC2A , or ERG11 gene point mutations. The echinocandin Candida mutants harbored fks mutations [ 14 , 15 , 17 , 21 , 24 , 27 , 36 , 37 , 38 ]. Some reports were for resistant/susceptible isolates, respectively, as well as for 101 and C. glabrata mutants and 55 WT isolates, respectively, are listed in Table 4 .…”