Molecular mechanism of viomycin inhibition of peptide elongation in bacteria.
Proc Natl Acad Sci U S A
; 113(4): 978-83, 2016 Jan 26.
Article
em En
| MEDLINE
| ID: mdl-26755601
ABSTRACT
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 â¼ 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Bactérias
/
Biossíntese de Proteínas
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Viomicina
/
Fator G para Elongação de Peptídeos
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Antibacterianos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article