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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 / Andrew T. Nishimoto; Nathan P. Wiederhold; Stephanie A. Flowers; Qing Zhang; Steven Kelly; Joachim Morschhäuser; Christopher M. Yates; William J. Hoekstra; Robert J. Schotzinger; Edward P. Garvey; P. David Rogers

Antimicrobial Agents and Chemotherapy

Swansea University Author: Steven, Kelly

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DOI (Published version): 10.1128/AAC.00341-19

Abstract

The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new 24 therapies to combat fungal infections, including Candida spp. To evaluate the in vitro activity of 25 these compounds in comparison to other available azoles, minimum inhibitory concentrations 26 (MICs) were de...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa49785
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Abstract: The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new 24 therapies to combat fungal infections, including Candida spp. To evaluate the in vitro activity of 25 these compounds in comparison to other available azoles, minimum inhibitory concentrations 26 (MICs) were determined for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and 27 posaconazole against 68 C. albicans clinical isolates well-characterized for azole resistance 28 mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 29 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.15 μg/mL) against 30 predominantly fluconazole-resistant isolates. However, five of 68 isolates exhibited MICs 31 greater than six dilutions (>2 μg/mL) to both tetrazoles compared to fluconazole-susceptible 32 isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit for all 33 triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in 34 one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 35 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated for 36 hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R), 37 but showed activity against strains with hyperactive forms of Mrr1 and Upc2. VT-1161 had 38 elevated MICs against a minority of clinical isolates that were more susceptible to itraconazole 39 (3), voriconazole (1), or posaconazole (5). While mutations affecting Erg3 activity appear to 40 greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for 41 four isolates could not be explained by known azole resistance mechanisms, suggesting the 42 presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol 43 demethylase inhibitors.
College: Swansea University Medical School