VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice

  • J Antimicrob Chemother. 2018 Aug 1;73(8):2089-2094. doi: 10.1093/jac/dky170.
Timothy J Break  1 ,  Jigar V Desai  1 ,  Kelley R Healey  2 ,  Mukil Natarajan  1 ,  Elise M N Ferre  1 ,  Christina Henderson  3 ,  Adrian Zelazny  3 ,  Ulrich Siebenlist  4 ,  Christopher M Yates  5 ,  Oren J Cohen  5 ,  Robert J Schotzinger  5 ,  David S Perlin  2 ,  Edward P Garvey  5 ,  Michail S Lionakis  1
Affiliations
  • 1. Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, National Institutes of Health, Bethesda, MD, USA.
  • 2. Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Science, Newark, NJ, USA.
  • 3. NIH Clinical Center/Department of Laboratory Medicine, Bethesda, MD, USA.
  • 4. Immune Activation Section, Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, MD, USA.
  • 5. Viamet Pharmaceuticals, Inc., Durham, NC, USA.
PMID: 29788070 DOI: 10.1093/jac/dky170
Abstract

Background: Chronic mucocutaneous candidiasis (CMC) treatment often induces drug resistance, posing long-term challenges. A novel broad-spectrum fungal CYP51 Inhibitor, VT-1598, specifically targets Fungal CYP51, but not human CYP Enzymes.

Objectives: To determine the efficacy of VT-1598 in the treatment of oral Candida Infection caused by fluconazole-susceptible and -resistant clinical isolates.

Methods: The MICs of VT-1598 and fluconazole for 28 Candida isolates recovered from patients with inherited CMC were determined using CLSI M27-A3 and M27-S4 guidelines. Plasma and tongue VT-1598 or fluconazole concentrations were measured in mice following oral administration to determine tissue distribution. Tongue Fungal load was determined in IL-17 signalling-deficient Act1-/- mice following sublingual Candida albicans Infection and oral treatment with fluconazole or VT-1598.

Results: Among the 28 Candida isolates, 10 (36%) had fluconazole MICs of ≥4 mg/L, whereas VT-1598 demonstrated potent in vitro activity against all isolates (MIC90, 0.125 mg/L). After oral administration, VT-1598 levels in mouse plasma and tongue were significantly greater than those of fluconazole. In vivo, VT-1598 exhibited significant efficacy against fluconazole-susceptible and -resistant C. albicans, even at low drug doses. Furthermore, after a 10 day washout period, tongue Fungal burdens in fluconazole-treated mice returned to vehicle control levels, whereas, in contrast, they were undetectable in mice treated with VT-1598.

Conclusions: VT-1598 effectively controls in vitro growth of mucosally derived Candida clinical isolates, including fluconazole-resistant strains. In vivo, VT-1598 eliminates C. albicans, even after a long washout period or at low doses. Therefore, VT-1598 is a promising drug candidate that may significantly improve treatment options for CMC patients.

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