Molecular mechanism of viomycin inhibition of peptide elongation in bacteria
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 4, 978-983 p.Article in journal (Refereed) PublishedText
Viomycin is a tuberactinomycin antibiotic essential for treating multi-drug-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 similar to 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.
Place, publisher, year, edition, pages
2016. Vol. 113, no 4, 978-983 p.
protein synthesis, viomycin, ribosome, antibiotics, tuberculosis
Microbiology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-277786DOI: 10.1073/pnas.1517541113ISI: 000368617900047PubMedID: 26755601OAI: oai:DiVA.org:uu-277786DiVA: diva2:905799