title: Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bürstner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Ostermann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Jutta
authors.initials: J
authors.lastname: Blank
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Cecile
authors.initials: C
authors.lastname: Delmas
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Freuler
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerhartz
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hinniger
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Liechty
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mihalic
authors.affiliation: Novartis Institutes for BioMedical Research Inc, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Pistorius
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: Novartis Institutes for BioMedical Research Inc, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Thomas
authors.affiliation: Novartis Institutes for BioMedical Research Inc, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056, Basel, Switzerland. esther.schmitt@novartis.com.
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000962:Antimalarials; D001426:Bacterial Proteins; D001688:Biological Products; D049071:Endopeptidase Clp; D009363:Neoplasm Proteins; D009842:Oligopeptides; D000099170:Bis(5'-adenosyl)triphosphatase; C459019:cyclomarin A
keywords: antiprotozoal agents; cyclomarin; diadenosine triphosphate; malaria; natural products