Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets

John M Bennett, Sunil K Narwal, Stephanie Kabeche, Daniel Abegg, Vandana Thathy, Fiona Hackett, Tomas Yeo, Veronica L Li, Ryan Muir, Franco Faucher, Scott Lovell, Michael J Blackman, Alexander Adibekian, Ellen Yeh, David A Fidock, Matthew Bogyo

Research output: Contribution to journalArticlepeer-review

Abstract

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. Our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are promising, synthetically tractable antimalarials.

Original languageEnglish
Pages (from-to)1714-1728.e10
JournalCell Chemical Biology
Volume31
Issue number9
Early online date12 Aug 2024
DOIs
Publication statusPublished - 19 Sept 2024

Bibliographical note

Copyright © 2024 Elsevier Ltd. All rights reserved.

Funding

This work was supported in part by the NIH ( R33 AI127581 , to DAF and MB, R01 AI109023 to D.A.F) and by Department of Defense grant ( W81XWH2210520 to D.F. and M.B.). V.L.L. was supported by NIH training grant T32 GM113854 . The work was also supported by funding to M.J.B. from the Wellcome Trust ( 220318/A/20/Z ) and the Francis Crick Institute ( https://www.crick.ac.uk/ ) which receives its core funding from Cancer Research UK ( CC2129 ), the UK Medical Research Council ( CC2129 ), and the Wellcome Trust ( CC2129 ). This work was in part by the NIH (R33 AH27581 to D.A.F. and M.B. R01 AI109023 to D.A.F.), the Bill and Melinda Gates Foundation (INV-033538 to D.A.F.), and the Department of Defense grant (W81XWII2210520 to D.A.F. and M.B.). V.L.L. was supported by NIH training grant T32 GM113854. The work was also supported by funding to M.J.B. from the Wellcome Trust (220318/A/20/Z) and the Francis Crick Institute (https://www.crick.ac.uk/) which receives its core funding from Cancer Research UK (CC2129), the UK Medical Research Council (CC2129), and the Wellcome Trust (CC2129). Conceptualization, J.M.B. and M.B; methodology, J.M.B. S.K.N. S.K. D.A.F. and M.B.; formal analysis, J.M.B. S.K.N. S.K. V.T. and T.Y.; investigation, J.M.B. S.K.N. S.K. D.A. V.T. F.H. T.Y. V.L.L. R.M. F.F. and S.L.; writing \u2013 original draft, J.M.B. S.K.N. D.A.F. and M.B.; writing \u2013 editing and revising, J.M.B. S.K.N. D.A.F. and M.B; visualization, J.M.B. S.K.N. and V.T.; supervision, M.J.B. A.A. E.Y. D.A.F. and M.B.; funding acquisition, D.A.F. and M.B. The authors declare no competing interests.

FundersFunder number
Medical Research Council
Francis Crick Institute
Cancer Research UKCC2129
U.S. Department of DefenseW81XWH2210520, T32 GM113854, W81XWII2210520
National Institutes of HealthR33 AH27581, R01 AI109023, R33 AI127581
Bill and Melinda Gates FoundationINV-033538
The Wellcome Trust220318/A/20/Z

Keywords

  • Plasmodium falciparum
  • activity-based probes
  • alky/aryl phosphonates
  • covalent probes
  • drug resistance
  • lipid metabolism
  • serine hydrolases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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