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J Biol Chem, Vol. 273, Issue 32, 20073-20077, August 7, 1998

Ketolide Resistance Conferred by Short Peptides

From the Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, Illinois 60607

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.

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