Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin.

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Akbergenov R, Shcherbakov D, Matt T, Duscha S, Meyer M, Wilson DN, Bottger EC

Molecular basis for the selectivity of antituberculosis compounds capreomycin and viomycin.

Antimicrob Agents Chemother. 2011 Oct;55(10):4712-7. doi: 10.1128/AAC.00628-11. Epub 2011 Jul 18.

PubMed ID

21768509 [ View in PubMed

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Abstract

Capreomycin and the structurally similar compound viomycin are cyclic peptide antibiotics which are particularly active against Mycobacterium tuberculosis, including multidrug 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 future resistance development, and propose mechanisms involved in tuberactinomycin ototoxicity, which may enable the development of improved, less-toxic derivatives.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Capreomycin	16S/23S rRNA (cytidine-2'-O)-methyltransferase TlyA	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Yes	Inhibitor	Details