Unraveling the Biology of a Fungal Meningitis Pathogen Using Chemical Genetics
Open accessAbstract
The fungal meningitis pathogen Cryptococcus neoformans is a central driver of mortality in HIV/AIDS. We report a genome-scale chemical genetic data map for this pathogen that quantifies the impact of 439 small-molecule challenges on 1,448 gene knockouts. We identified chemical phenotypes for 83% of mutants screened and at least one genetic response for each compound. C. neoformans chemical-genetic responses are largely distinct from orthologous published profiles of Saccharomyces cerevisiae, demonstrating the importance of pathogen-centered studies. We used the chemical-genetic matrix to predict novel pathogenicity genes, infer compound mode of action, and to develop an algorithm, O2M, that predicts antifungal synergies. These predictions were experimentally validated, thereby identifying virulence genes, a molecule that triggers G2/M arrest and inhibits the Cdc25 phosphatase, and many compounds that synergize with the antifungal drug fluconazole. Our work establishes a chemical-genetic foundation for approaching an infection responsible for greater than one-third of AIDS-related deaths.
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A high-throughput approach, termed the overlap2 method, has been developed to predict synergistic and antagonistic drug pairs using at least one known synergistic drug pair and chemical-genetic data sets.
“A high-throughput approach has been developed to predict synergistic and antagonistic drug pairs using at least one known synergistic drug pair and chemical–genetic data sets118,119.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [118]
The overlap2 method applied to a compound library enriched for FDA-approved compounds against C. neoformans predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.
“For example, the overlap2 method was applied to a compound library enriched for FDA-approved compounds against C. neoformans116–119 and successfully predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [118]
Pathogen-specific analyses revealed that many compounds display species-specific chemical-genetic interactions.
“Chemical–genetic mapping of synergistic compound pairs has been explored in Saccharomyces cerevisiae, but pathogen-specific analyses have revealed that many compounds display species-specific chemical–genetic interactions118.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [118]
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References 66 · Cited by 84
Research works printed but not linked: 1
- WHO 2011 Rapid Advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents, and children W.H.O. Library Geneva, Switzerland WHO Press 26110194
- Authors
- Brown, J. C. S., Nelson, J., VanderSluis, B., Deshpande, R., Butts, A., Kagan, S., Polacheck, I., Krysan, D. J., Myers, C. L., & Madhani, H. D.
- Affiliations
- University of California, San Francisco (US)
- University of Minnesota (US)
- University of Rochester Medicine (US)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Myers, Chad L.
- Madhani, Hiten D.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 159
- Issue
- 5
- Pages
- 1168-1187
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4243055
- OpenAlex
- W2149579582
- Cited by
- 84
- References
- 66
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 6
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Canadian Institute for Advanced Research
- National Institutes of Health
- National Human Genome Research Institute (R01HG005084)
- National Institute of General Medical Sciences (R01GM104975, 1R01GM04975)
- National Institute of Allergy and Infectious Diseases (R01AI096869, R01AI099206, R01AI091422, R01AI100272, T32AI060537)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- Cryptococcus neoformans, fungal meningitis, chemical genetics, gene knockout, virulence genes, fluconazole, Cdc25 phosphatase, G2/M cell cycle arrest, HIV mortality, Saccharomyces cerevisiae comparison
- MeSH terms
- Algorithms, Animals, Antifungal Agents, Cryptococcus neoformans, Microbial Sensitivity Tests, Saccharomyces cerevisiae, AIDS-Related Opportunistic Infections, Virulence Factors, Gene Knockout Techniques, Drug Discovery
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