2.50
Hdl Handle:
http://hdl.handle.net/10033/338489
Title:
Antimalarial activity of the myxobacterial macrolide chlorotonil a.
Authors:
Held, Jana; Gebru, Tamirat; Kalesse, Markus; Jansen, Rolf; Gerth, Klaus; Müller, Rolf; Mordmüller, Benjamin
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.
Citation:
Antimalarial activity of the myxobacterial macrolide chlorotonil a. 2014, 58 (11):6378-84 Antimicrob. Agents Chemother.
Journal:
Antimicrobial agents and chemotherapy
Issue Date:
Nov-2014
URI:
http://hdl.handle.net/10033/338489
DOI:
10.1128/AAC.03326-14
PubMed ID:
25114138
Type:
Article
Language:
en
ISSN:
1098-6596
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorHeld, Janaen
dc.contributor.authorGebru, Tamiraten
dc.contributor.authorKalesse, Markusen
dc.contributor.authorJansen, Rolfen
dc.contributor.authorGerth, Klausen
dc.contributor.authorMüller, Rolfen
dc.contributor.authorMordmüller, Benjaminen
dc.date.accessioned2015-01-16T14:40:57Z-
dc.date.available2015-01-16T14:40:57Z-
dc.date.issued2014-11-
dc.identifier.citationAntimalarial activity of the myxobacterial macrolide chlorotonil a. 2014, 58 (11):6378-84 Antimicrob. Agents Chemother.en
dc.identifier.issn1098-6596-
dc.identifier.pmid25114138-
dc.identifier.doi10.1128/AAC.03326-14-
dc.identifier.urihttp://hdl.handle.net/10033/338489-
dc.description.abstractMyxobacteria 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.en
dc.language.isoenen
dc.titleAntimalarial activity of the myxobacterial macrolide chlorotonil a.en
dc.typeArticleen
dc.identifier.journalAntimicrobial agents and chemotherapyen

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