Cyclopropyl Carboxamides with Potent Antimalarial Activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB75780 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13302168_1.fastq.gz | Fastqsanger.gz | |||
| ERR13302168_2.fastq.gz | Fastqsanger.gz | |||
| ERR13302169_1.fastq.gz | Fastqsanger.gz | |||
| ERR13302169_2.fastq.gz | Fastqsanger.gz | |||
| ERR13302170_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 20 |
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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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Project description:Bacteria modify expression of different types of terminal oxidase in response to oxygen availability. Corynebacterium glutamicum, a facultative anaerobic bacterium in Actinobacteria, possesses aa3-type cytochrome c oxidase and cytochrome bd-type quinol oxidase, the latter of which is induced upon oxygen limitation. We report here that an extracytoplasmic function sigma factor, SigC, is unprecedentedly responsible for the regulation. Chromatin immunoprecipitation in conjunction with microarray (ChIP-chip) analysis detected eight SigC-binding regions in the genome, leading to identification of a consensus promoter sequence for SigC recognition. The promoter sequences were found upstream of genes for cytochrome bd, heme a synthesis enzymes, and uncharacterized membrane proteins, all of which were upregulated by sigC overexpression. In contrast, that found on the antisense strand upstream of an operon encoding the cytochrome bc1 complex conferred a SigC-dependent negative effect on the operon expression. The SigC regulon was induced by cytochrome aa3 deficiency without modification of expression of sigC itself, but not by deficiency of the bc1 complex. These findings suggest that SigC is activated in response to impairment of electron transfer via cytochrome aa3, not directly to shift in oxygen levels. Our results provide a novel paradigm for transcriptional regulation of the aerobic respiratory system in bacteria.
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