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Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin


Akbergenov, R; Shcherbakov, D; Matt, T; Duscha, S; Meyer, Martin; Wilson, D N; Böttger, E C (2011). Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin. Antimicrobial Agents and Chemotherapy, 55(10):4712-4717.

Abstract

Capreomycin and the structurally similar compound viomycin are cyclic peptide antibiotics which are particularly active against Mycobacterium tuberculosis, including multi-drug resistant strains. Both antibiotics bind across the ribosomal interface involving 23S rRNA helix 69 (H69) and 16S rRNA helix 44 (h44). The binding site of tuberactinomycins in h44 partially overlaps with that of aminoglycosides and they share with these drugs the side effect of irreversible hearing loss. Here we studied the drug-target interaction on ribosomes modified by site-directed mutagenesis. We identified rRNA residues in h44 as the main determinants of phylogenetic selectivity, predict compensatory evolution to impact on future resistance development and propose mechanisms involved in tuberactinomycin ototoxicity which may enable the development of improved less toxic derivatives.

Abstract

Capreomycin and the structurally similar compound viomycin are cyclic peptide antibiotics which are particularly active against Mycobacterium tuberculosis, including multi-drug resistant strains. Both antibiotics bind across the ribosomal interface involving 23S rRNA helix 69 (H69) and 16S rRNA helix 44 (h44). The binding site of tuberactinomycins in h44 partially overlaps with that of aminoglycosides and they share with these drugs the side effect of irreversible hearing loss. Here we studied the drug-target interaction on ribosomes modified by site-directed mutagenesis. We identified rRNA residues in h44 as the main determinants of phylogenetic selectivity, predict compensatory evolution to impact on future resistance development and propose mechanisms involved in tuberactinomycin ototoxicity which may enable the development of improved less toxic derivatives.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:14 Sep 2011 09:22
Last Modified:03 Aug 2017 15:31
Publisher:American Society for Microbiology
ISSN:0066-4804
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/AAC.00628-11
PubMed ID:21768509

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