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.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Robbins
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Michaela
authors.initials: M
authors.lastname: Spitzer
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Tennison
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC H3G 1A4, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Cerone
authors.affiliation: Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Averette
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
authors.affiliation: Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.affiliation: Department of Medicine, McGill University, Montréal, QC H3G 1A4, Canada.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sheppard
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Pavillon Montréal, QC H3C 3J7, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: wrightge@mcmaster.ca.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D002991:Clofazimine / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012568:Schizosaccharomyces / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D002991:Clofazimine