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

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

doi:10.1021/acsinfecdis.4c00284

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Number of pages	16
Journal	ACS Infectious Diseases
Early online date	18 Jul 2024
DOIs	https://doi.org/10.1021/acsinfecdis.4c00284
Publication status	E-pub ahead of print - 18 Jul 2024

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Cite this

Alpizar-Sosa, E. A., 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. (2024). Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach. ACS Infectious Diseases. Advance online publication. https://doi.org/10.1021/acsinfecdis.4c00284

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

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.",

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Alpizar-Sosa, EA, Zimbres, FM, Mantilla, BS, Dickie, EA, Wei, W, Burle-Caldas, GA, Filipe, LNS, Van Bocxlaer, K , Price, HP, Ibarra-Meneses, AV, Beaudry, F, Fernandez-Prada, C, Whitfield, PD, Barrett, MP & Denny, PW 2024, 'Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach', ACS Infectious Diseases. https://doi.org/10.1021/acsinfecdis.4c00284

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AU - Alpizar-Sosa, Edubiel A

AU - Zimbres, Flavia M

AU - Mantilla, Brian S

AU - Dickie, Emily A

AU - Wei, Wenbin

AU - Burle-Caldas, Gabriela A

AU - Filipe, Laura N S

AU - Van Bocxlaer, Katrien

AU - Price, Helen P

AU - Ibarra-Meneses, Ana V

AU - Beaudry, Francis

AU - Fernandez-Prada, Christopher

AU - Whitfield, Philip D

AU - Barrett, Michael P

AU - Denny, Paul W

PY - 2024/7/18

Y1 - 2024/7/18

N2 - 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.

AB - 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.

U2 - 10.1021/acsinfecdis.4c00284

DO - 10.1021/acsinfecdis.4c00284

M3 - Article

C2 - 39023360

SN - 2373-8227

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

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