Simwela, N. V., Guiguemde, W. A., Straimer, J., Regnault, C., Yokokawa, F., Taft, B., Diagana, T. T., Barrett, M. P. and Waters, A. P. (2023) A conserved metabolic signature associated with response to fast-acting anti-malarial agents. Microbiology Spectrum, 11(6), e0397622. (doi: 10.1128/spectrum.03976-22) (PMID:37800971) (PMCID:PMC10714989)
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Abstract
Characterizing the mode of action of anti-malarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of anti-malarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone. A slow-acting anti-malarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5-h window of drug exposure. In contrast, fast-killing drugs, DHA and the spiroindolone (NITD246), elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of hemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described class of anti-malarial agents of the 5-aryl-2-amino-imidazothiadiazole class also exhibited a fast-acting profile that featured peptide losses indicative of disrupted hemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast-acting anti-malarial compounds generate similar biochemical signatures in Plasmodium pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by grants from the Wellcome Trust to A.P.W (083811/Z/07/Z; 107046/Z/15/Z). M.P.B. is funded by a Wellcome Trust core grant to the Wellcome Centre for Integrative Parasitology (104111/Z/14/Z). N.V.S was funded by a Commonwealth Doctoral Studentship (MWCS-2017-789) and the Novartis Global Health Fellowships. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Regnault, Clement and Simwela, Nelson and Barrett, Professor Michael and Waters, Professor Andy |
| Authors: | Simwela, N. V., Guiguemde, W. A., Straimer, J., Regnault, C., Yokokawa, F., Taft, B., Diagana, T. T., Barrett, M. P., and Waters, A. P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Microbiology Spectrum |
| Publisher: | American Society for Microbiology |
| ISSN: | 2165-0497 |
| ISSN (Online): | 2165-0497 |
| Published Online: | 06 October 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Microbiology Spectrum 11(6): e0397622 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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