VT-1161 protects mice against oropharyngeal candidiasis caused by fluconazole-susceptible and -resistant Candida albicans
Open accessAbstract
BACKGROUND: Candida albicans, the most common human fungal pathogen, causes chronic mucosal infections in patients with inborn errors of IL-17 immunity that rely heavily on chronic, often lifelong, azole antifungal agents for treatment. However, a rise in azole resistance has predicated a need for developing new antifungal drugs. OBJECTIVES: To test the in vitro and in vivo efficacy of VT-1161 and VT-1129 in the treatment of oropharyngeal candidiasis with azole-susceptible or -resistant C. albicans strains. METHODS: MICs of VT-1161, VT-1129 and nine licensed antifungal drugs were determined for 31 Candida clinical isolates. The drug concentrations in mouse serum and tongues were measured following oral administration. IL-17-signalling-deficient Act1-/- mice were infected with fluconazole-susceptible or fluconazole-resistant C. albicans strains, and the amount of mucosal fungal burden was determined after fluconazole or VT-1161 treatment. RESULTS: Fourteen isolates (45%) were not fluconazole susceptible (MIC ≥4 mg/L). VT-1161 and VT-1129 showed significant in vitro activity against the majority of the 31 mucosal clinical isolates (MIC50 0.03 and 0.06 mg/L, respectively), including Candida glabrata (MIC50, 0.125 and 0.25 mg/L, respectively). After oral doses, VT-1161 and VT-1129 concentrations in mouse serum and tongues were well above their MIC50 values. VT-1161 was highly effective as treatment of both fluconazole-susceptible and -resistant oropharyngeal candidiasis in Act1-/- mice. CONCLUSIONS: VT-1129 and VT-1161 exhibit significant in vitro activity against Candida strains, including fluconazole-resistant C. albicans and C. glabrata. VT-1161 administration in mice results in significant mucosal drug accumulation and eradicates infection caused by fluconazole-susceptible and -resistant Candida strains.
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VT-1161 is active against fluconazole-resistant C. glabrata strains.
“As a consequence, VT-1161 is active against fluconazole-resistant C. glabrata strains [116,117]”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [117]
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- Authors
- Break, T. J., Desai, J. V., Natarajan, M., Ferre, E. M. N., Henderson, C., Zelazny, A. M., Siebenlist, U., Hoekstra, W. J., Schotzinger, R. J., Garvey, E. P., & Lionakis, M. S.
- Affiliations
- National Institutes of Health (US)
- Fungal Pathogenesis Unit, Laboratory of Clinical Immunology & Microbiology, NIAID, National Institutes of Health, Bethesda, MD, USA
- Viamet Pharmaceuticals (United States) (US)
- Corresponding author
- Lionakis, Michail S
- ORCID
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-10-10
- Volume
- 73
- Issue
- 1
- Pages
- 151-155
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- PMC
- PMC5890729
- OpenAlex
- W2762367458
- Cited by
- 34
- References
- 19
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 1 · 2019: 3 · 2018: 5
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- NIH
- NIAID
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- oropharyngeal candidiasis, Candida albicans, Candida glabrata, fluconazole resistance, azole antifungals, antifungal drug development, antifungal susceptibility, oral antifungal therapy
- MeSH terms
- Animals, Antifungal Agents, Candida albicans, Candidiasis, Oral, Humans, Microbial Sensitivity Tests, Pyridines, Tetrazoles, Fluconazole, Mice, Knockout, Drug Resistance, Fungal, Candida glabrata, Adaptor Proteins, Signal Transducing, Mice
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