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Ketolide resistance conferred by short peptides
S Tripathi1, P S Kloss, A S Mankin
1Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, Illinois 60607, USA.
Abstract:
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.
Insights
Researchers identified a pentapeptide (MRFFV) that confers high resistance to the ketolide antibiotic HMR3004. This peptide may displace antibiotics from the ribosome, enabling continued protein synthesis.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Resistance
Background:
- Macrolide antibiotics are crucial for treating bacterial infections.
- Antibiotic resistance, particularly to macrolides, poses a significant global health threat.
- Understanding resistance mechanisms is vital for developing new therapeutic strategies.
Purpose of the Study:
- To identify novel peptides that confer resistance to ketolide antibiotics.
- To elucidate the mechanism of action for macrolide resistance peptides.
- To propose a model for peptide-antibiotic interaction at the ribosomal level.
Main Methods:
- Selection of resistant clones from a random pentapeptide mini-gene library.
- Identification of the highest-resistance conferring pentapeptide (MRFFV).
- Comparative analysis of amino acid sequences of resistance peptides against different macrolides.
Main Results:
- The pentapeptide MRFFV conferred the highest level of resistance to the ketolide HMR3004.
- A correlation was observed between peptide sequences and macrolide antibiotic structures.
- Evidence suggests peptide-drug interaction on the ribosome.
Conclusions:
- A "bottle brush" model is proposed, where resistance peptides displace macrolide antibiotics from the ribosome.
- This displacement mechanism allows for the continuation of protein synthesis in the presence of antibiotics.
- Findings offer insights into novel strategies for combating macrolide resistance.