In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides

Heather L. Mead, Michael Valentine, Holly Yin, George R. Thompson, Paul Keim, David M. Engelthaler, Bridget M. Barker

Research output: Contribution to journalArticlepeer-review

Abstract

Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease.

Original languageEnglish (US)
Article number01008-24
JournalMicrobiology spectrum
Volume12
Issue number10
DOIs
StatePublished - Oct 2024

Keywords

  • Coccidioides
  • Valley Fever
  • adjunctive agent
  • antifungal therapy
  • antifungal therapy
  • coccidioidomycosis
  • fungal infection
  • sertraline

ASJC Scopus subject areas

  • Physiology
  • Ecology
  • General Immunology and Microbiology
  • Genetics
  • Microbiology (medical)
  • Cell Biology
  • Infectious Diseases

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