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

Nicole Robbins, Michaela Spitzer, Tennison Yu, Robert P. Cerone, Anna K. Averette, Yong Sun Bahn, Joseph Heitman, Donald C. Sheppard, Mike Tyers, Gerard D. Wright

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Abstract

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.

Original languageEnglish
Pages (from-to)1481-1492
Number of pages12
JournalCell Reports
Volume13
Issue number7
DOIs
Publication statusPublished - 2015 Nov 17

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Robbins, N., Spitzer, M., Yu, T., Cerone, R. P., Averette, A. K., Bahn, Y. S., Heitman, J., Sheppard, D. C., Tyers, M., & Wright, G. D. (2015). An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens. Cell Reports, 13(7), 1481-1492. https://doi.org/10.1016/j.celrep.2015.10.018