Ketolide Resistance Conferred by Short Peptides

Clones expressing pentapeptides conferring resistance to a ketolide antibiotic, HMR3004, were selected from a random pentapeptide mini-gene library. The pentapeptide MRFFV conferred the highest level of resistance and was encoded in three different mini-genes. Comparison of amino acid sequences of p...

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Bibliographic Details
Published in:The Journal of biological chemistry 1998-08, Vol.273 (32), p.20073-20077
Main Authors: Tripathi, Shaila, Kloss, Patricia S., Mankin, Alexander S.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Drug Resistance - genetics
Erythromycin - pharmacology
Escherichia coli - drug effects
Ketolides
Macrolides
Models, Biological
Molecular Structure
Peptide Library
Peptides - chemistry
Ribosomes - metabolism
Sequence Analysis
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Summary:Clones expressing pentapeptides conferring resistance to a ketolide antibiotic, HMR3004, were selected from a random pentapeptide mini-gene library. The pentapeptide MRFFV conferred the highest level of resistance and was encoded in three different mini-genes. Comparison of amino acid sequences of peptides conferring resistance to a ketolide with those conferring resistance to erythromycin reveals a correspondence between the peptide sequence and the chemical structure of macrolide antibiotic, indicating possible interaction between the peptide and the drug on the ribosome. Based on these observations, a “bottle brush” model of action of macrolide resistance peptides is proposed, in which newly translated peptide interacts with the macrolide molecule on the ribosome and actively displaces it from its binding site. Temporal “cleaning” of the ribosome from the bound antibiotic may be sufficient to allow continuation of protein synthesis even despite the presence of the drug in the medium.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.273.32.20073