Broad antifungal resistance mediated by RNAi-dependent epimutation in the basal human fungal pathogen Mucor circinelloides
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Abstract
Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.
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In M. circinelloides, RNAi-mediated epimutations can confer antifungal resistance via degradation of mRNAs of drug target genes.
“In Mucor circinelloides (causative agent of mucormycosis), RNAi (RNA interference)-mediated epimutations can confer antifungal resistance via degradation of mRNAs of drug target genes100,101.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [100]
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Molecular mechanisms governing antifungal drug resistance
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- Authors
- Chang, Z., Billmyre, R. B., Lee, S. C., & Heitman, J.
- Affiliations
- Duke University (US)
- Stowers Institute for Medical Research (US)
- Corresponding author
- Chang, Zanetta
- Heitman, Joseph
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-02-11
- Volume
- 15
- Issue
- 2
- Pages
- e1007957
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC6386414
- OpenAlex
- W2949320128
- Cited by
- 72
- References
- 56
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 10 · 2022: 8 · 2021: 6 · 2020: 12 · 2019: 5
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Update notices
- new_version (2019-02-22)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Astellas Pharma
- National Institutes of Health (2r01ai050113-16a1, AI39115, AI39115-21, AI50113, AI50113-15)
- National Institute of General Medical Sciences (T32GM007171)
- National Institute of Allergy and Infectious Diseases (R37AI039115, AI39115-21, AI50113-15, AI 39115, AI50113, R01-AI050113, AI104533, P01AI104533)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Mucor circinelloides, mucormycosis, antifungal resistance, epimutations, RNA interference, small RNA, pyrG, 5-fluoroorotic acid resistance, rapamycin resistance, gene silencing, fungal pathogenesis
- MeSH terms
- Antifungal Agents, Genes, Fungal, Humans, Mucor, Mucormycosis, Mutation, Orotate Phosphoribosyltransferase, Orotic Acid, Orotidine-5'-Phosphate Decarboxylase, RNA, Fungal, Tacrolimus, Sirolimus, Drug Resistance, Multiple, Fungal, RNA Interference, Epigenesis, Genetic
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