Antimalarial activity of the myxobacterial macrolide chlorotonil A

verfasst von

Jana Held, Tamirat Gebru, Markus Kalesse, Rolf Jansen, Klaus Gerth, Rolf Müller, Benjamin Mordmüller

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.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

Eberhard Karls Universität Tübingen
Centre de Recherches Médicales de Lambaréné (CERMEL)
Deutsches Zentrum für Infektionsforschung (DZIF)
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universität des Saarlandes

Typ

Artikel

Journal

Antimicrobial Agents and Chemotherapy

Band

58

Seiten

6378-6384

Anzahl der Seiten

7

ISSN

0066-4804

Publikationsdatum

01.11.2014

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Pharmakologie, Pharmakologie (medizinische), Infektionskrankheiten

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1128/AAC.03326-14 (Zugang: Offen)