A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets
Abstract
Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here, we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by incorporating proteomic and lipidomic analyses. We performed genetic complementation and overexpression of H. capsulatum genes in Saccharomyces cerevisiae to validate reactions identified in the map and to determine enzymes responsible for catalyzing orphan reactions. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We found that the sphingolipid biosynthesis inhibitor myriocin, the fatty acid desaturase inhibitor thiocarlide, and the fatty acid analog 10-thiastearic acid inhibit H. capsulatum growth in nanomolar to low-micromolar concentrations. These compounds also reduced the intracellular infection in an alveolar macrophage cell line. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development.
- Authors:
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[1];
[2];
[2];
[2];
[4];
[2];
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- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA, Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
- Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
- Department of Biology, Brigham Young University, Provo, Utah, USA
- Hematology Laboratory, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Chemistry, North Carolina State University, Raleigh, North Carolina, USA
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1832247
- Alternate Identifier(s):
- OSTI ID: 1836231
- Report Number(s):
- PNNL-SA-152496
Journal ID: ISSN 2150-7511; e02972-21
- Grant/Contract Number:
- AC05-76RL01830; R21 AI124797; P42 ES027704
- Resource Type:
- Published Article
- Journal Name:
- mBio (Online)
- Additional Journal Information:
- Journal Name: mBio (Online) Journal Volume: 12 Journal Issue: 6; Journal ID: ISSN 2150-7511
- Publisher:
- American Society for Microbiology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Histoplasma capsulatum; lipid metabolism; drug target; platelet-activating factor; multi-omics analysis
Citation Formats
Zamith-Miranda, Daniel, Heyman, Heino M., Burnet, Meagan C., Couvillion, Sneha P., Zheng, Xueyun, Munoz, Nathalie, Nelson, William C., Kyle, Jennifer E., Zink, Erika M., Weitz, Karl K., Bloodsworth, Kent J., Clair, Geremy, Zucker, Jeremy D., Teuton, Jeremy R., Payne, Samuel H., Kim, Young-Mo, Reyes Gil, Morayma, Baker, Erin S., Bredeweg, Erin L., Nosanchuk, Joshua D., Nakayasu, Ernesto S., and Kronstad, ed., James W. A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets. United States: N. p., 2021.
Web. doi:10.1128/mBio.02972-21.
Zamith-Miranda, Daniel, Heyman, Heino M., Burnet, Meagan C., Couvillion, Sneha P., Zheng, Xueyun, Munoz, Nathalie, Nelson, William C., Kyle, Jennifer E., Zink, Erika M., Weitz, Karl K., Bloodsworth, Kent J., Clair, Geremy, Zucker, Jeremy D., Teuton, Jeremy R., Payne, Samuel H., Kim, Young-Mo, Reyes Gil, Morayma, Baker, Erin S., Bredeweg, Erin L., Nosanchuk, Joshua D., Nakayasu, Ernesto S., & Kronstad, ed., James W. A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets. United States. https://doi.org/10.1128/mBio.02972-21
Zamith-Miranda, Daniel, Heyman, Heino M., Burnet, Meagan C., Couvillion, Sneha P., Zheng, Xueyun, Munoz, Nathalie, Nelson, William C., Kyle, Jennifer E., Zink, Erika M., Weitz, Karl K., Bloodsworth, Kent J., Clair, Geremy, Zucker, Jeremy D., Teuton, Jeremy R., Payne, Samuel H., Kim, Young-Mo, Reyes Gil, Morayma, Baker, Erin S., Bredeweg, Erin L., Nosanchuk, Joshua D., Nakayasu, Ernesto S., and Kronstad, ed., James W. Tue .
"A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets". United States. https://doi.org/10.1128/mBio.02972-21.
@article{osti_1832247,
title = {A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets},
author = {Zamith-Miranda, Daniel and Heyman, Heino M. and Burnet, Meagan C. and Couvillion, Sneha P. and Zheng, Xueyun and Munoz, Nathalie and Nelson, William C. and Kyle, Jennifer E. and Zink, Erika M. and Weitz, Karl K. and Bloodsworth, Kent J. and Clair, Geremy and Zucker, Jeremy D. and Teuton, Jeremy R. and Payne, Samuel H. and Kim, Young-Mo and Reyes Gil, Morayma and Baker, Erin S. and Bredeweg, Erin L. and Nosanchuk, Joshua D. and Nakayasu, Ernesto S. and Kronstad, ed., James W.},
abstractNote = {Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here, we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by incorporating proteomic and lipidomic analyses. We performed genetic complementation and overexpression of H. capsulatum genes in Saccharomyces cerevisiae to validate reactions identified in the map and to determine enzymes responsible for catalyzing orphan reactions. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We found that the sphingolipid biosynthesis inhibitor myriocin, the fatty acid desaturase inhibitor thiocarlide, and the fatty acid analog 10-thiastearic acid inhibit H. capsulatum growth in nanomolar to low-micromolar concentrations. These compounds also reduced the intracellular infection in an alveolar macrophage cell line. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development.},
doi = {10.1128/mBio.02972-21},
journal = {mBio (Online)},
number = 6,
volume = 12,
place = {United States},
year = {Tue Dec 21 00:00:00 EST 2021},
month = {Tue Dec 21 00:00:00 EST 2021}
}
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