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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 .
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 May 24; Vol. 63 (6). Date of Electronic Publication: 2019 May 24 (Print Publication: 2019). - Publication Year :
- 2019
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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 ≤0.15 μg/ml) against predominantly fluconazole-resistant (≥8 μg/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (>2 μg/ml) to both tetrazoles compared to fluconazole-susceptible 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.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Candida albicans genetics
Drug Resistance, Fungal genetics
Fluconazole pharmacology
Fungal Proteins genetics
Humans
Microbial Sensitivity Tests methods
Mutation genetics
Transcription Factors genetics
Antifungal Agents pharmacology
Azoles pharmacology
Candida albicans drug effects
Drug Resistance, Fungal drug effects
Pyridines pharmacology
Tetrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 63
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 30910896
- Full Text :
- https://doi.org/10.1128/AAC.00341-19