Summary of project PR000829
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000829. The data can be accessed directly via it's Project DOI: 10.21228/M8HX2M This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR000829 |
| Project DOI: | doi: 10.21228/M8HX2M |
| Project Title: | Antimalarial pantothenamide metabolites target acetyl-CoA biosynthesis in Plasmodium falciparum |
| Project Summary: | Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage Plasmodium falciparum parasites and that block transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties and cleared parasites in a humanized mouse infection model of P. falciparum. Metabolomics revealed that CoA biosynthetic enzymes converted pantothenamides into CoA-analogs that interfered with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11. Introduction and reversion of these mutations in P. falciparum by CRISPR/Cas9 gene editing confirmed the key roles of these enzymes in the sensitivity of the malaria parasite to pantothenamides. These pantothenamide compounds with a unique mode of action may have potential as drugs against malaria parasites. |
| Institute: | Pennsylvania State University |
| Last Name: | Llinás |
| First Name: | Manuel |
| Address: | W126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA |
| Email: | mul27@psu.edu |
| Phone: | (814) 867-3527 |
| Publications: | https://stm.sciencemag.org/content/11/510/eaas9917 DOI: 10.1126/scitranslmed.aas9917 |
Summary of all studies in project PR000829
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST001238 | P falciparum asexual metabolomics following drug treatment (part-I) | Plasmodium falciparum | Pennsylvania State University | MS | 2019-09-23 | 1 | 18 | Uploaded data (3.6G)* |
| ST001239 | NMR assignment of synthetic pantothenamides (part-II) | Synthetic | Pennsylvania State University | NMR | 2019-09-23 | 1 | 13 | Uploaded data (24.3M)* |
