Recapitulation in Saccharomyces cerevisiae of Cytochrome b Mutations Conferring Resistance to Atovaquone in Pneumocystis jiroveci
Open accessAbstract
Pneumocystis jiroveci (human-derived P. carinii ) is an opportunistic pathogenic fungus which causes pneumonia and is life-threatening in immunocompromised individuals. Spontaneously acquired resistance to atovaquone, a hydroxynaphthoquinone that is used to treat P. jiroveci infections, was linked to mutations in the mitochondrially encoded cytochrome b gene. Because P. jiroveci cannot be easily cultivated, we have developed Saccharomyces cerevisiae as an alternative system to study atovaquone resistance mutations. In this work, we introduced seven mutations linked with atovaquone resistance in P. jiroveci into the S. cerevisiae cytochrome b gene. The effects of the mutations on the respiratory function and on the sensitivity to the inhibitor were then characterized. Six of the reported mutations lowered the sensitivity of the S. cerevisiae bc 1 complex to atovaquone, while one mutation had no effect on the drug resistance. These results were confirmed by monitoring the in vivo resistance of S. cerevisiae mutants which carried both the cytochrome b mutations and a deletion of the ABC transporter genes, allowing the drug to bypass the weakened efflux pump system. S. cerevisiae thus provides an easy-to-use system to characterize in vivo and in vitro cytochrome b mutations reported in pathogens and to assess their role in drug resistance.
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The S. cerevisiae cytochrome b mutants F129L, L275F, F278A and Y279C were previously generated using mitochondrial transformation.
“These mutants were previously generated using the mitochondrial transformation technique [51].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant <i>Candida auris</i> (2024) · cites this paper as [51]
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- Authors
- Hill, P., Kessl, J., Fisher, N., Meshnick, S., Trumpower, B. L., & Meunier, B.
- Affiliations
- University College London (GB)
- Dartmouth College (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Trumpower, Bernard L.
- Meunier, Brigitte
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2003-09
- Volume
- 47
- Issue
- 9
- Pages
- 2725-2731
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC182622
- OpenAlex
- W2133852460
- Cited by
- 68
- References
- 17
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 5 · 2012: 4
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council
- National Institute of General Medical Sciences (GM 20379, R37GM020379, R01GM020379)
- National Institute of Allergy and Infectious Diseases (R01AI046966, AI46966)
- Topics
- Health Sciences › Medicine › Epidemiology › Pneumocystis jirovecii pneumonia detection and treatment
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- atovaquone resistance, Pneumocystis jirovecii, cytochrome b mutations, bc1 complex, Saccharomyces cerevisiae model, hydroxynaphthoquinones, electron transport chain, drug efflux, antifungal resistance, Pneumocystis carinii pneumonia
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Cytochrome b Group, Microbial Sensitivity Tests, Models, Molecular, Molecular Sequence Data, Mutation, Naphthoquinones, Oxygen Consumption, Pneumocystis, Protein Conformation, Saccharomyces cerevisiae, Mutagenesis, Site-Directed, Drug Resistance, Fungal, Atovaquone
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