Investigating the entire course of telithromycin binding to Escherichia coli ribosomes.

Nucleic Acids Research
Ourania N KostopoulouDimitrios L Kalpaxis

Abstract

Applying kinetics and footprinting analysis, we show that telithromycin, a ketolide antibiotic, binds to Escherichia coli ribosomes in a two-step process. During the first, rapidly equilibrated step, telithromycin binds to a low-affinity site (K(T) = 500 nM), in which the lactone ring is positioned at the upper portion of the peptide exit tunnel, while the alkyl-aryl side chain of the drug inserts a groove formed by nucleotides A789 and U790 of 23S rRNA. During the second step, telithromycin shifts slowly to a high-affinity site (K(T)* = 8.33 nM), in which the lactone ring remains essentially at the same position, while the side chain interacts with the base pair U2609:A752 and the extended loop of protein L22. Consistently, mutations perturbing either the base pair U2609:A752 or the L22-loop hinder shifting of telithromycin to the final position, without affecting the initial step of binding. In contrast, mutation Lys63Glu in protein L4 placed on the opposite side of the tunnel, exerts only a minor effect on telithromycin binding. Polyamines disfavor both sequential steps of binding. Our data correlate well with recent crystallographic data and rationalize the changes in the accessibility of ribosomes to telithromycin in respo...Continue Reading

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Citations

Mar 26, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Marios KrokidisGeorge P Dinos
Aug 19, 2015·Journal of Computational Chemistry·Anna Pavlova, James C Gumbart
Jun 19, 2014·Nucleic Acids Research·Ourania N KostopoulouDimitrios L Kalpaxis
Nov 6, 2013·Antimicrobial Agents and Chemotherapy·Marios G KrokidisGeorge P Dinos
Jan 15, 2020·Proceedings of the National Academy of Sciences of the United States of America·Maxim S SvetlovAlexander S Mankin
Dec 13, 2017·Proceedings of the National Academy of Sciences of the United States of America·Maxim S SvetlovAlexander S Mankin
Sep 4, 2021·The Journal of Antimicrobial Chemotherapy·Ian BoostromOwen B Spiller

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Methods Mentioned

BETA
NMR
footprinting

Software Mentioned

SPSS

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