Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach

Alpizar-Sosa, EdubielA.; Zimbres, Flavia M.; Mantilla, Brian S.; Dickie, Emily A.; Wei, Wenbin; Burle-Caldas, Gabriela A.; Filipe, Laura N. S.; Van Bocxlaer, Katrien; Price, Helen P.; Ibarra-Meneses, Ana V.; Beaudry, Francis; Fernandez-Prada, Christopher; Whitfield, Philip D.; Barrett, Michael P.; Denny, Paul W.

Abstract

The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo. Here we sought to further examine the target of this compound in the more tractable species L. mexicana, using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding LmxIPCS had little impact in vitro, it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit LmxIPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.

Citation

Alpizar-Sosa, E., Zimbres, F. M., Mantilla, B. S., Dickie, E. A., Wei, W., Burle-Caldas, G. A., Filipe, L. N. S., Van Bocxlaer, K., Price, H. P., Ibarra-Meneses, A. V., Beaudry, F., Fernandez-Prada, C., Whitfield, P. D., Barrett, M. P., & Denny, P. W. (in press). Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach. ACS Infectious Diseases, 10(8), 2913-2928. https://doi.org/10.1021/acsinfecdis.4c00284

• Journal Article Type: Article
• Acceptance Date: Jul 3, 2024
• Online Publication Date: Jul 18, 2024
• Deposit Date: Aug 22, 2024
• Publicly Available Date: Aug 22, 2024
• Journal: ACS Infectious Diseases
• Electronic ISSN: 2373-8227
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 8
• Pages: 2913-2928
• DOI: https://doi.org/10.1021/acsinfecdis.4c00284
• Keywords: Leishmania, thermal proteomic profiling, clemastine fumarate, inositol phosphorylceramide synthase, polyomics, CRISPR-Cas9
• Public URL: https://keele-repository.worktribe.com/output/885244
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00284