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. 2011 May;5(5):e1161.
doi: 10.1371/journal.pntd.0001161. Epub 2011 May 24.

Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma

Sven N Hobbie  1 , Marcel Kaiser, Sebastian Schmidt, Dmitri Shcherbakov, Tanja Janusic, Reto Brun, Erik C Böttger
Affiliations

Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma

Sven N Hobbie et al. PLoS Negl Trop Dis. 2011 May.

Abstract

Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compounds bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an experimental model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in-vitro ribosomal assays to that of in-vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Secondary-structure comparison of small-subunit rRNA sequences.
Phylogenetic comparison of the rRNA helices that correspond to the proximal portion of helix 44 in bacterial 16S rRNA, which is an integral part of the ribosomal decoding site.
Figure 2
Figure 2. Aminoglycoside susceptibility of rRNA chimeras.
Aminoglycoside susceptibility is expressed as minimal inhibitory concentrations (MIC, µg/mL). The protozoan sequence part is boxed with the protozoan-specific nucleotides colored in blue.
See this image and copyright information in PMC

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