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Antimicrobial Agents and Chemotherapy, August 2005, p. 3251-3255, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3251-3255.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mitochondrial Ribosome as the Target for the Macrolide Antibiotic Clarithromycin in the Helminth Echinococcus multilocularis

Alexander Mathis,^1* Peter Wild,² Erik C. Boettger,³ Christian M. O. Kapel,⁴ and Peter Deplazes¹

Institute of Parasitology,¹ Electron Microscopy Unit, Institutes of Veterinary Anatomy and of Virology, University of Zürich, Winterthurerstrasse 266A, 8057 Zürich, Switzerland,² Institut für Medizinische Mikrobiologie, University of Zürich, Gloriastr. 30/32, 8006 Zürich, Switzerland,³ Danish Centre for Experimental Parasitology, The Royal Veterinary and Agricultural University, Dyrlaegevej 100, 1870 Frederiksberg C, Denmark⁴

Received 28 February 2005/ Returned for modification 7 April 2005/ Accepted 27 April 2005

The mitochondrial rRNA of the tapeworm species Echinococcus multilocularis carries an adenine at sequence position 2058 (numbering according to that for Escherichia coli) of the large-subunit rRNA (lsrRNA), while the nucleus-encoded rRNA, as determined in this study, is characterized by 2058G. This indicates a dichotomy in the drug susceptibilities of ribosomes: cytoplasmic ribosomes are predicted to be resistant to macrolide antibiotics, while mitochondrial ribosomes lack the most common chromosomal resistance determinant, lsrRNA 2058G. Upon incubation with the macrolide clarithromycin, the formation of vesicles from metacestode tissue was reduced in a dose-dependent manner. Electron microscopy revealed distinct morphological alterations both of the mitochondria and of the vesicle wall (e.g., loss of microtriches) in drug-treated vesicles. Adult worms lost their motility and displayed morphological changes (shortening and constriction of proglottids and the presence of vacuoles) upon incubation with clarithromycin. Our findings demonstrate that macrolides have distinct in vitro effects on E. multilocularis, endorsing the use of sequence-based in silico approaches for exploitation of available ribosomal drugs as anthelmintic agents.

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* Corresponding author. Mailing address: Institute of Parasitology, University of Zürich, Winterthurerstrasse 266A, Zürich 8057, Switzerland Phone: 41-44-6358536. Fax: 41-44-6358907. E-mail: address:alexander.mathis{at}access.unizh.ch.

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Antimicrobial Agents and Chemotherapy, August 2005, p. 3251-3255, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3251-3255.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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