Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA
10.1128/jb.183.23.6898-6907.2001
Crossref journal-article
American Society for Microbiology
Journal of Bacteriology (235)
Abstract

ABSTRACTMacrolides represent a clinically important class of antibiotics that block protein synthesis by interacting with the large ribosomal subunit. The macrolide binding site is composed primarily of rRNA. However, the mode of interaction of macrolides with rRNA and the exact location of the drug binding site have yet to be described. A new class of macrolide antibiotics, known as ketolides, show improved activity against organisms that have developed resistance to previously used macrolides. The biochemical reasons for increased potency of ketolides remain unknown. Here we describe the first mutation that confers resistance to ketolide antibiotics while leaving cells sensitive to other types of macrolides. A transition of U to C at position 2609 of 23S rRNA renderedE. colicells resistant to two different types of ketolides, telithromycin and ABT-773, but increased slightly the sensitivity to erythromycin, azithromycin, and a cladinose-containing derivative of telithromycin. Ribosomes isolated from the mutant cells had reduced affinity for ketolides, while their affinity for erythromycin was not diminished. Possible direct interaction of ketolides with position 2609 in 23S rRNA was further confirmed by RNA footprinting. The newly isolated ketolide-resistance mutation, as well as 23S rRNA positions shown previously to be involved in interaction with macrolide antibiotics, have been modeled in the crystallographic structure of the large ribosomal subunit. The location of the macrolide binding site in the nascent peptide exit tunnel at some distance from the peptidyl transferase center agrees with the proposed model of macrolide inhibitory action and explains the dominant nature of macrolide resistance mutations. Spatial separation of the rRNA residues involved in universal contacts with macrolides from those believed to participate in structure-specific interactions with ketolides provides the structural basis for the improved activity of the broader spectrum group of macrolide antibiotics.

Bibliography

Garza-Ramos, G., Xiong, L., Zhong, P., & Mankin, A. (2001). Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA. Journal of Bacteriology, 183(23), 6898–6907.

Authors 4
  1. Georgina Garza-Ramos (first)
  2. Liqun Xiong (additional)
  3. Ping Zhong (additional)
  4. Alexander Mankin (additional)
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Dates
Type When
Created 23 years ago (July 27, 2002, 6:01 a.m.)
Deposited 1 year, 7 months ago (Jan. 5, 2024, 7:07 p.m.)
Indexed 1 month ago (July 16, 2025, 7:52 a.m.)
Issued 23 years, 8 months ago (Dec. 1, 2001)
Published 23 years, 8 months ago (Dec. 1, 2001)
Published Print 23 years, 8 months ago (Dec. 1, 2001)
Funders 0

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@article{Garza_Ramos_2001, title={Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA}, volume={183}, ISSN={1098-5530}, url={http://dx.doi.org/10.1128/jb.183.23.6898-6907.2001}, DOI={10.1128/jb.183.23.6898-6907.2001}, number={23}, journal={Journal of Bacteriology}, publisher={American Society for Microbiology}, author={Garza-Ramos, Georgina and Xiong, Liqun and Zhong, Ping and Mankin, Alexander}, year={2001}, month=dec, pages={6898–6907} }