PT  - JOURNAL ARTICLE
AU  - Daniel Zamith-Miranda
AU  - Heino M. Heyman
AU  - Meagan C. Burnet
AU  - Sneha P. Couvillion
AU  - Xueyun Zheng
AU  - Nathalie Munoz
AU  - William C. Nelson
AU  - Jennifer E. Kyle
AU  - Erika M. Zink
AU  - Karl K. Weitz
AU  - Kent J. Bloodsworth
AU  - Geremy Clair
AU  - Jeremy D. Zucker
AU  - Jeremy R. Teuton
AU  - Samuel H. Payne
AU  - Young-Mo Kim
AU  - Morayma Reyes Gil
AU  - Erin S. Baker
AU  - Erin L. Bredeweg
AU  - Joshua D. Nosanchuk
AU  - Ernesto S. Nakayasu
TI  - A <em>Histoplasma capsulatum</em> lipid metabolic map identifies antifungal targets
AID  - 10.1101/2020.03.02.973412
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.03.02.973412
4099  - http://biorxiv.org/content/early/2021/10/25/2020.03.02.973412.short
4100  - http://biorxiv.org/content/early/2021/10/25/2020.03.02.973412.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.