An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.

Published

Journal Article

There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil with ∼3,600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole-resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode of action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Additional tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens.

Full Text

Duke Authors

Cited Authors

  • Robbins, N; Spitzer, M; Yu, T; Cerone, RP; Averette, AK; Bahn, Y-S; Heitman, J; Sheppard, DC; Tyers, M; Wright, GD

Published Date

  • November 17, 2015

Published In

Volume / Issue

  • 13 / 7

Start / End Page

  • 1481 - 1492

PubMed ID

  • 26549450

Pubmed Central ID

  • 26549450

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.10.018

Language

  • eng

Conference Location

  • United States