5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus
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Abstract
Patients infected with the fungal pathogen Cryptococcus are most effectively treated with a combination of 5-fluorocytosine (5FC) and amphotericin B. 5FC acts as a prodrug, which is converted into toxic 5-fluorouracil (5FU) upon uptake into fungal cells. However, the pathogen frequently develops resistance through unclear mechanisms. Here we show that resistance to 5FC in Cryptococcus deuterogattii is acquired more frequently in isolates with defects in DNA mismatch repair that confer an elevated mutation rate. We use whole genome sequencing of 16 independent isolates to identify mutations associated with 5FC resistance in vitro. We find mutations in known resistance genes (FUR1 and FCY2 ) and in a gene UXS1 , previously shown to encode an enzyme that converts UDP-glucuronic acid to UDP-xylose for capsule biosynthesis, but not known to play a role in 5FC metabolism. Mutations in UXS1 lead to accumulation of UDP-glucuronic acid and alterations in nucleotide metabolism, which appear to suppress toxicity of both 5FC and its toxic derivative 5FU.
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A subset of Cryptococcus isolates have been identified as hypermutator strains, which contain mutations in core genes in the DNA mismatch repair pathway, most notably MSH2.
“a subset of Cryptococcus isolates have been identified as hypermutator strains30,31, which contain mutations in core genes in the DNA mismatch repair pathway, most notably MSH2 (refs30,32,33)”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [32]
Hypermutator strains have a 15% higher rate of resistance to flucytosine in C. gattii when compared with isolates that do not possess a hypermutator mutation.
“hypermutator strains have a 15% higher rate of resistance to this prodrug (the active drug is fluorouracil) when compared with isolates that do not possess a hypermutator mutation.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [32]
Hypermutator isolates derived from both the clinic and the laboratory lead to the rapid emergence of resistance to drugs such as rapamycin, FK506, flucytosine, fluconazole and even amphotericin B.
“hypermutator isolates derived from both the clinic and the laboratory lead to the rapid emergence of resistance to drugs such as rapamycin, FK506 (ref.33), flucytosine32, fluconazole and even amphotericin B30.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [32]
The enhanced flucytosine resistance in hypermutator strains was caused by loss-of-function mutations in Fcy2 and Fur1, and a mutation in Uxs1.
“This enhanced resistance was caused by loss-of-function mutations in the genes encoding the purine-cytosine permease Fcy2 and the uracil phosphoribosyltransferase Fur1, which import and process the prodrug, respectively, as well as a mutation in the gene encoding Uxs1, which produces UDP-xylose, a precursor in capsule biosynthesis32.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [32]
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References 52 · Cited by 102
- Authors
- Billmyre, R. B., Applen Clancey, S., Li, L. X., Doering, T. L., & Heitman, J.
- Affiliations
- Stowers Institute for Medical Research (US)
- Washington University in St. Louis (US)
- Duke University (US)
- Corresponding author
- Heitman, Joseph
- Venue
- Nature Communications
- Published
- 2020-01-08
- Volume
- 11
- Issue
- 1
- Pages
- 127-127
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6949227
- OpenAlex
- W3000052441
- Cited by
- 102
- References
- 52
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 17 · 2023: 14 · 2022: 19 · 2021: 19 · 2020: 10 · 2019: 1
- FWCI
- 11.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI120339, AI109623, AI39115-21, AI50113-15, AI112595-04, AI104533-05)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- 5-fluorocytosine resistance, Cryptococcus deuterogattii, DNA mismatch repair, hypermutation, capsule biosynthesis, UXS1, UDP-glucuronic acid, UDP-xylose, 5-fluorouracil toxicity, nucleotide metabolism, antifungal resistance, fungal pathogens
- MeSH terms
- Amphotericin B, Antifungal Agents, Cryptococcus, Flucytosine, Fungal Proteins, Humans, Microbial Sensitivity Tests, Mutation, Polysaccharides, Drug Resistance, Fungal
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