The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris

Nathan P. Wiederhold, Shawn R. Lockhart, Laura K. Najvar, Elizabeth L. Berkow, Rosie Jaramillo, Marcos Olivo, Edward P. Garvey, Christopher M. Yates, Robert J. Schotzinger, Gabriel Catano, Thomas F. Patterson

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris. Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 g/ml and MICs ranging from 0.03 to 8 g/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and 21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10 CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.

Original languageEnglish (US)
Article numbere02233-18
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • Candida auris
  • In vitro susceptibility
  • Invasive candidiasis
  • Murine model
  • VT-1598

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Wiederhold, N. P., Lockhart, S. R., Najvar, L. K., Berkow, E. L., Jaramillo, R., Olivo, M., Garvey, E. P., Yates, C. M., Schotzinger, R. J., Catano, G., & Patterson, T. F. (2019). The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris. Antimicrobial agents and chemotherapy, 63(3), [e02233-18]. https://doi.org/10.1128/AAC.02233-18