Project description:The increasing incidence of antimalarial drug resistance to the first-line artemisinins, and their combination partner drugs, underpins an urgent need for new antimalarial drugs, ideally with a novel mechanism of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum, low cytotoxicity, potent in vivo efficacy against murine malaria, and favourable preclinical pharmacokinetics, including a lengthy plasma elimination half-life. This study demonstrates the application of a “multi-omics” workflow based on high resolution orbitrap mass spectrometry to investigate the impact of JPC-3210 on biochemical pathways within P. falciparum infected red blood cells. Metabolomics and peptidomics analysis revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a depletion in short hemoglobin-derived peptides, while peptidomics analysis showed a depletion in longer hemoglobin-derived peptides. In order to further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerisation assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerisation, about 10-fold less potent then the quinoline antimalarials. Furthermore, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature in comparison to other known antimalarials. Whilst JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. In conclusion, multi-omics studies using high resolution mass spectrometry revealed JPC-3210 to possess a unique mechanism of action involving inhibition of hemoglobin digestion, depletion of DNA replication and synthesis proteins, and elevation of regulators of protein translation. Importantly, this mechanism is distinct from currently-used antimalarials, suggesting that JPC-3210 warrants further investigation as a potentially useful new antimalarial agent.

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Determination of mode of action of anti-malalrial drugs using untargeted metabolomics

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