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Antimalarial activity of the myxobacterial macrolide chlorotonil a.

Held, Jana
; 
Gebru, Tamirat
; 
Kalesse, Markus
; 
Jansen, Rolf
; 
Gerth, Klaus
; ; 
Mordmüller, Benjamin
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2014-11
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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.
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Antimicrobial agents and chemotherapy
URI
http://hdl.handle.net/10033/338489
DOI
10.1128/AAC.03326-14
PubMed ID
25114138
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Article
Language
en
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1098-6596
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publications of the research group of microbial natural substances([HIPS]MINS)