Alpizar-Sosa, Edubiel A, Zimbres, Flavia M, Mantilla, Brian S et al. (12 more authors) (2024) Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach. ACS Infectious Diseases. ISSN 2373-8227
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 08 Aug 2024 09:30 |
Last Modified: | 24 Oct 2024 00:21 |
Published Version: | https://doi.org/10.1021/acsinfecdis.4c00284 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1021/acsinfecdis.4c00284 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:215875 |
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Description: alpizar-sosa-et-al-2024-evaluation-of-the-leishmania-inositol-phosphorylceramide-synthase-as-a-drug-target-using-a
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