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

doi:10.1016/j.celrep.2015.10.018

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

Research output: Contribution to journal › Article › peer-review

58 Citations (Scopus)

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 language	English
Pages (from-to)	1481-1492
Number of pages	12
Journal	Cell Reports
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2015.10.018
Publication status	Published - 2015 Nov 17

Bibliographical note

Funding Information:
We thank Leah Cowen for strains and Leah Cowen, Troy Ketela, and G.D.W.’s lab members for helpful discussions. N.R. was supported by the Michael G. DeGroote Postdoctoral Fellowship Award and a Canadian Institute for Health Research (CIHR) Fellowship. G.D.W. and M.T. were supported by Canada Research Chairs in Antibiotic Biochemistry and Systems and Synthetic Biology respectively. Research was funded by grants from CIHR (MOP 119572 to M.T. and G.D.W.), the European Research Council (SCG-233457 to M.T.), the NIH (1R01-AI112595 to J.H.) and Wellcome Trust (085178 to M.T.).

Publisher Copyright:
© 2015 The Authors.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2015.10.018

Cite this

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

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.",

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

note = "Funding Information: We thank Leah Cowen for strains and Leah Cowen, Troy Ketela, and G.D.W.{\textquoteright}s lab members for helpful discussions. N.R. was supported by the Michael G. DeGroote Postdoctoral Fellowship Award and a Canadian Institute for Health Research (CIHR) Fellowship. G.D.W. and M.T. were supported by Canada Research Chairs in Antibiotic Biochemistry and Systems and Synthetic Biology respectively. Research was funded by grants from CIHR (MOP 119572 to M.T. and G.D.W.), the European Research Council (SCG-233457 to M.T.), the NIH (1R01-AI112595 to J.H.) and Wellcome Trust (085178 to M.T.). Publisher Copyright: {\textcopyright} 2015 The Authors.",

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AU - Averette, Anna K.

AU - Bahn, Yong Sun

AU - Heitman, Joseph

AU - Sheppard, Donald C.

AU - Tyers, Mike

AU - Wright, Gerard D.

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N2 - 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.

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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