title: Antimalarial activity of the myxobacterial macrolide chlorotonil a.
abstract: Myxobacteria are Gram-negative soil-dwelling bacteria belonging to the phylum Proteobacteria. They are a rich source of promising compounds for clinical application, such as epothilones for cancer therapy and several new antibiotics. In the course of a bioactivity screening program of secondary metabolites produced by Sorangium cellulosum strains, the macrolide chlorotonil A was found to exhibit promising antimalarial activity. Subsequently, we evaluated chlorotonil A against Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Chlorotonil A was highly active, with a 50% inhibitory concentration between 4 and 32 nM; additionally, no correlations between the activities of chlorotonil A and artesunate (rho, 0.208) or chloroquine (rho, -0.046) were observed. Per os treatment of Plasmodium berghei-infected mice with four doses of as little as 36 mg of chlorotonil A per kg of body weight led to the suppression of parasitemia with no obvious signs of toxicity. Chlorotonil A acts against all stages of intraerythrocytic parasite development, including ring-stage parasites and stage IV to V gametocytes, and it requires only a very short exposure to the parasite to exert its antimalarial action. Conclusively, chlorotonil A has an exceptional and unprecedented profile of action and represents an urgently required novel antimalarial chemical scaffold. Therefore, we propose it as a lead structure for further development as an antimalarial chemotherapeutic.
authors.affiliation: Institute of Tropical Medicine, Eberhard Karls University, Tübingen, Germany Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon German Centre for Infection Research, Germany janaheld@hotmail.de.
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.affiliation: Institute of Tropical Medicine, Eberhard Karls University, Tübingen, Germany German Centre for Infection Research, Germany.
authors.forename: Tamirat
authors.initials: T
authors.lastname: Gebru
authors.affiliation: Institute of Organic Chemistry, Leibniz Universität Hannover, Hannover, Germany Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kalesse
authors.affiliation: German Centre for Infection Research, Germany Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Gerth
authors.affiliation: German Centre for Infection Research, Germany Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Tropical Medicine, Eberhard Karls University, Tübingen, Germany Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon German Centre for Infection Research, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002738:Chloroquine / Q000494:pharmacology; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009231:Myxococcales / Q000378:metabolism; D018512:Parasitemia / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D006843:Hydrocarbons, Chlorinated; D018942:Macrolides; C526339:chlorotonil A; D000077332:Artesunate; D002738:Chloroquine
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