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Gift from nature : cyclomarin s kills Mycobacteria and malaria parasites by distinct modes of action

Bürstner, Nathalie and Roggo, Silvio and Ostermann, Nils and Blank, Jutta and Delmas, Cecile and Freuler, Felix and Gerhartz, Bernd and Hinniger, Alexandra and Hoepfner, Dominic and Liechty, Brigitta and Mihalic, Manuel and Murphy, Jason and Pistorius, Dominik and Rottmann, Matthias and Thomas, Jason R. and Schirle, Markus and Schmitt, Esther K.. (2015) Gift from nature : cyclomarin s kills Mycobacteria and malaria parasites by distinct modes of action. ChemBioChem, 16 (17). pp. 2433-2436.

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Official URL: http://edoc.unibas.ch/41838/

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Abstract

Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics. Using a biochemical assay, we could show that cyclomarin A is a specific inhibitor of the plasmodial enzyme but not of the closest human homologue hFHIT. Co-crystallisation experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme⋅substrate complex. These results validate PfAp3Aase as a new drug target for the treatment of malaria. We have previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is a rare example of a natural product with two distinct and specific modes of action.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Publisher:Wiley-VCH
ISSN:1439-4227
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:30 Jun 2016 11:02
Deposited On:19 Apr 2016 08:38

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