The structures of the anti-tuberculosis antibiotics viomycin and capreomycin bound to the 70S ribosome

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Abstract
The tuberactinomycin antibiotic family is one of the most effective against multi-drug resistant M. tuberculosis. The structures of two members of this family, viomycin and capreomycin, bound to the ribosome now indicate that they act by stabilizing the A site tRNA in a pre-translocation state and may suggest further avenues for drug development. Viomycin and capreomycin belong to the tuberactinomycin family of antibiotics, which are among the most effective antibiotics against multidrug-resistant tuberculosis. Here we present two crystal structures of the 70S ribosome in complex with three tRNAs and bound to either viomycin or capreomycin at 3.3- and 3.5-Å resolution, respectively. Both antibiotics bind to the same site on the ribosome, which lies at the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit. The structures of these complexes suggest that the tuberactinomycins inhibit translocation by stabilizing the tRNA in the A site in the pretranslocation state. In addition, these structures show that the tuberactinomycins bind adjacent to the binding sites for the paromomycin and hygromycin B antibiotics, which may enable the development of new derivatives of tuberactinomycins that are effective against drug-resistant strains.