An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens
Open accessAbstract
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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Clofazimine is a broad-spectrum adjuvant therapy capable of acting synergistically with both caspofungin and fluconazole against C. neoformans, among other fungal species.
“A study assessing the combination of known antifungals with ~3,600 bioactive compounds identified clofazimine as a broad-spectrum adjuvant therapy that is capable of acting synergistically with both caspofungin and fluconazole against C. neoformans, among other fungal species115”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [115]
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References 37 · Cited by 78
- Authors
- 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.
- Affiliations
- Michael G. DeGroote Institute for Infectious Disease Research (CA)
- McGill University (CA)
- Yonsei University (KR)
- Duke University (US)
- Institute for Research in Immunology and Cancer (CA)
- Corresponding author
- Wright, Gerard D.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 13
- Issue
- 7
- Pages
- 1481-1492
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4654976
- OpenAlex
- W1929821956
- Cited by
- 78
- References
- 37
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 12 · 2019: 4 · 2018: 8 · 2017: 15 · 2016: 11 · 2015: 1
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by-nc-nd)
- eScholarship@McGill (McGill) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Wellcome Trust (085178, 233457)
- Canada Research Chairs
- National Institutes of Health (5r01ai112595-04)
- Canadian Institutes of Health Research (119572_1)
- National Institute of Allergy and Infectious Diseases (R01-AI112595, 1R01-AI112595)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- combination antifungal therapy, fluconazole resistance, Candida albicans, clofazimine, synergistic effect, chemical genetics, Aspergillus fumigatus, fungal infection, drug repurposing
- MeSH terms
- Antifungal Agents, Candida albicans, Clofazimine, Cryptococcus neoformans, Drug Combinations, Drug Synergism, Microbial Sensitivity Tests, Saccharomyces cerevisiae, Schizosaccharomyces
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