The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates
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Resistance to the commonly used azole antifungal fluconazole (FLC) can develop due to overexpression of ATP-binding cassette (ABC) and major facilitator superfamily (MFS) plasma membrane transporters. An approach to overcoming this resistance is to identify inhibitors of these efflux pumps. We have developed a pump assay suitable for high-throughput screening (HTS) that uses recombinant Saccharomyces cerevisiae strains hyperexpressing individual transporters from the opportunistic fungal pathogen Candida albicans . The recombinant strains possess greater resistance to azoles and other pump substrates than the parental host strain. A flow cytometry-based HTS, which measured increased intracellular retention of the fluorescent pump substrate rhodamine 6G (R6G) within yeast cells, was used to screen the Prestwick Chemical Library (PCL) of 1,200 marketed drugs. Nine compounds were identified as hits, and the monoamine oxidase A inhibitor (MAOI) clorgyline was identified as an inhibitor of two C. albicans ABC efflux pumps, CaCdr1p and CaCdr2p. Secondary in vitro assays confirmed inhibition of pump-mediated efflux by clorgyline. Clorgyline also reversed the FLC resistance of S. cerevisiae strains expressing other individual fungal ABC transporters ( Candida glabrata Cdr1p or Candida krusei Abc1p) or the C. albicans MFS transporter Mdr1p. Recombinant strains were also chemosensitized by clorgyline to other azoles (itraconazole and miconazole). Importantly, clorgyline showed synergy with FLC against FLC-resistant C. albicans clinical isolates and a C. glabrata strain and inhibited R6G efflux from a FLC-resistant C. albicans clinical isolate. Clorgyline is a novel broad-spectrum inhibitor of two classes of fungal efflux pumps that acts synergistically with azoles against azole-resistant C. albicans and C. glabrata strains.
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Clorgyline is active against C. albicans and C. glabrata, where it inhibits efflux pumps and positively interacts with fluconazole.
“Clorgyline, a MAOI, is active against C. albicans and C. glabrata where it inhibits efflux pumps and positively interacts with fluconazole [56,70].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [70]
The activity of C. albicans transporters overexpressed in multi-drug-resistant strains and expressed in S. cerevisiae can be inhibited by clorgyline.
“This idea is supported by the observation that the activity of C. albicans transporters overexpressed in multi-drug-resistant strains and expressed in S. cerevisiae, can be inhibited by the antidepressants clorgyline [70].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [70]
Clorgyline is a broad-spectrum inhibitor of several fungal efflux pumps at 5.1 μM (1.4 μg/mL).
“| Clorgyline (MonoAmine Oxidase Inhibitor) | C. albicans, C. glabrata | 5.1 µM (1.4 µg/mL) | Broad-spectrum inhibitor of several with fluconazole fungal efflux pumps, displays a synergistic interaction | [56,70] |”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [70]
Clorgyline displays a synergistic interaction with fluconazole against C. albicans and C. glabrata at 5.1 μM (1.4 μg/mL).
“| Clorgyline (MonoAmine Oxidase Inhibitor) | C. albicans, C. glabrata | 5.1 µM (1.4 µg/mL) | Broad-spectrum inhibitor of several with fluconazole fungal efflux pumps, displays a synergistic interaction | [56,70] |”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [70]
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- Authors
- Holmes, A. R., Keniya, M. V., Ivnitski-Steele, I., Monk, B. C., Lamping, E., Sklar, L. A., & Cannon, R. D.
- Affiliations
- University of Otago (NZ)
- New Mexico Center for Molecular Discovery, University of New Mexico, Albuquerque, New Mexico, USA
- University of New Mexico (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-03
- Volume
- 56
- Issue
- 3
- Pages
- 1508-1515
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3294898
- OpenAlex
- W2139173424
- Cited by
- 106
- References
- 56
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 17 · 2019: 6 · 2018: 3 · 2017: 11 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 3
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH-084690, R03MH087406, U54MH084690)
- National Institute of Dental and Craniofacial Research (R01DE016885)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- clorgyline, monoamine oxidase A inhibitors, azole resistance, Candida albicans, Candida glabrata, ABC transporters, major facilitator superfamily, efflux pump inhibitors, fluconazole resistance, drug repurposing, antifungal synergy, high-throughput screening, clinical isolates
- MeSH terms
- Antifungal Agents, Biological Transport, Candida albicans, Clorgyline, Drug Synergism, Flow Cytometry, Fluorescent Dyes, Humans, Microbial Sensitivity Tests, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Rhodamines, Saccharomyces cerevisiae, Fluconazole, Gene Expression, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Organisms, Genetically Modified, Candida glabrata, Small Molecule Libraries, High-Throughput Screening Assays
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