Molecular mechanism of viomycin inhibition of peptide elongation in bacteria.

Mikael Holm, Anneli Borg, Måns Ehrenberg, Suparna Sanyal

Proceedings of the National Academy of Sciences of the United States of America 2016 Jan 26

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Viomycin is a tuberactinomycin antibiotic essential for treating multidrug-resistant tuberculosis. It inhibits bacterial protein synthesis by blocking elongation factor G (EF-G) catalyzed translocation of messenger RNA on the ribosome. Here we have clarified the molecular aspects of viomycin inhibition of the elongating ribosome using pre-steady-state kinetics. We found that the probability of ribosome inhibition by viomycin depends on competition between viomycin and EF-G for binding to the pretranslocation ribosome, and that stable viomycin binding requires an A-site bound tRNA. Once bound, viomycin stalls the ribosome in a pretranslocation state for a minimum of ∼ 45 s. This stalling time increases linearly with viomycin concentration. Viomycin inhibition also promotes futile cycles of GTP hydrolysis by EF-G. Finally, we have constructed a kinetic model for viomycin inhibition of EF-G catalyzed translocation, allowing for testable predictions of tuberactinomycin action in vivo and facilitating in-depth understanding of resistance development against this important class of antibiotics.

Citation

Mikael Holm, Anneli Borg, Måns Ehrenberg, Suparna Sanyal. Molecular mechanism of viomycin inhibition of peptide elongation in bacteria. Proceedings of the National Academy of Sciences of the United States of America. 2016 Jan 26;113(4):978-83