Mitochondrial ribosome as the target for the macrolide antibiotic clarithromycin in the helminth Echinococcus multilocularis.
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.
Mathis
Alexander
A
Institute of Parasitology, University of Zürich, Winterthurerstrasse 266A, Zürich 8057, Switzerland. alexander.mathis@access.unizh.ch
Wild
Peter
P
Boettger
Erik C
EC
Kapel
Christian M O
CM
Deplazes
Peter
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017291:Clarithromycin / Q000494:pharmacology*; D048210:Echinococcus multilocularis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D018942:Macrolides / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D010458:Peptidyl Transferases / Q000187:drug effects / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects*; D017422:Sequence Analysis, DNA
D000900:Anti-Bacterial Agents; D018942:Macrolides; D012335:RNA, Ribosomal; D010458:Peptidyl Transferases; D017291:Clarithromycin