Lipid Flippase Subunit Cdc50 Mediates Drug Resistance and Virulence in Cryptococcus neoformans
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Cryptococcus neoformans is a human fungal pathogen and a major cause of fungal meningitis in immunocompromised individuals. Treatment options for cryptococcosis are limited. Of the two major antifungal drug classes, azoles are active against C. neoformans but exert a fungistatic effect, necessitating long treatment regimens and leaving open an avenue for emergence of azole resistance. Drugs of the echinocandin class, which target the glucan synthase and are fungicidal against a number of other fungal pathogens, such as Candida species, are ineffective against C. neoformans . Despite the sensitivity of the target enzyme to the drug, the reasons for the innate resistance of C. neoformans to echinocandins remain unknown. To understand the mechanism of echinocandin resistance in C. neoformans , we screened gene disruption and gene deletion libraries for mutants sensitive to the echinocandin-class drug caspofungin and identified a mutation of CDC50 , which encodes the β-subunit of membrane lipid flippase. We found that the Cdc50 protein localized to membranes and that its absence led to plasma membrane defects and enhanced caspofungin penetration into the cell, potentially explaining the increased caspofungin sensitivity. Loss of CDC50 also led to hypersensitivity to the azole-class drug fluconazole. Interestingly, in addition to functioning in drug resistance, CDC50 was also essential for fungal resistance to macrophage killing and for virulence in a murine model of cryptococcosis. Furthermore, the surface of cdc50Δ cells contained increased levels of phosphatidylserine, which has been proposed to act as a macrophage recognition signal. Together, these results reveal a previously unappreciated role of membrane lipid flippase in C. neoformans drug resistance and virulence. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that is the most common cause of fungal meningitis, causing over 620,000 deaths annually. The treatment options for cryptococcosis are very limited. The most commonly used drugs are either fungistatic (azoles) or highly toxic (amphotericin B). Echinocandins are the newest fungicidal drug class that works well in treating candidiasis and aspergillosis, yet they are ineffective in treating cryptococcosis. In this study, we showed that the regulatory subunit of the lipid translocase (flippase), a protein that regulates the asymmetrical orientation of membrane lipids, is required for C. neoformans resistance to caspofungin, as well as for virulence during infection. This discovery identifies lipid flippase as a potential C. neoformans drug target, which plays an important role in the innate resistance of C. neoformans to echinocandins and in fungal virulence.
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Altered susceptibility to echinocandins is connected with stress responses that result in paradoxical growth at high drug concentrations and elevated cell wall chitin content.
“Altered susceptibility to echinocandins is also connected with stress responses that result in paradoxical growth of the microorganism at high concentrations of the drugs and elevated cell wall chitin content [110,111].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [111]
A genetic screen of more than 10,000 C. neoformans mutants identified CDC50 as integral to echinocandin resistance and demonstrated its involvement in maintaining lipid asymmetry of the phospholipid membrane.
“A genetic screen of more than 10,000 C. neoformans mutants provided insight into this inherent resistance46. This screen identified CDC50 (encoding the β-subunit of a lipid flippase enzyme) as integral to echinocandin resistance and further demonstrated its involvement in maintaining lipid asymmetry of the phospholipid membrane46.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [46]
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Combating increased antifungal drug resistance in Cryptococcus, what should we do in the future?
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Lipid Transport by <i>Candida albicans</i> Dnf2 Is Required for Hyphal Growth and Virulence
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Self-citationP4-ATPase subunit Cdc50 plays a role in yeast budding and cell wall integrity in Candida glabrata
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Impacts of P4‐ATPase Deletion on Membrane Asymmetry and Disease Development
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- Authors
- Huang, W., Liao, G., Baker, G. M., Wang, Y., Lau, R., Paderu, P., Perlin, D. S., & Xue, C.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Xue, Chaoyang
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2016-07-06
- Volume
- 7
- Issue
- 3
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4959666
- OpenAlex
- W2358244203
- Cited by
- 88
- References
- 59
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 17 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 7 · 2016: 2
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Charles and Johanna Busch Memorial Fund
- Chinese Scholarship Council
- HHS | National Institutes of Health (AI113368, AI115204, AI109025)
- American Heart Association (12SDG9110034)
- 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
- Cryptococcus neoformans, lipid flippase, echinocandin resistance, caspofungin, azole resistance, fluconazole, cryptococcosis, virulence, macrophage killing, phosphatidylserine, plasma membrane, fungal drug resistance, fungal meningitis
- MeSH terms
- Caspofungin, Animals, Antifungal Agents, Cell Membrane, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, Fungal Proteins, Humans, Mutation, Phosphatidylserines, Virulence, Fluconazole, Gene Deletion, Drug Resistance, Fungal, Phospholipid Transfer Proteins, Mice, Echinocandins, Lipopeptides
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