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First published on July 27, 2006; DOI: 10.1124/mol.106.026567

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Received for publication May 12, 2006.
Revised July 27, 2006.
Accepted for publication July 27, 2006.

On the mechanism of action of 9-O-arylalkyloxime derivatives of 6-O-mycaminosyltylonolide, a new class of 16-membered macrolide antibiotics

Panagiotis Karahalios 1, Dimitrios L Kalpaxis 1, Hong Fu 2, Leonard Katz 2, Daniel N Wilson 3, George P. Dinos 4*

1 University of Patras 2 Kosan Biosciences Inc 3 MPI fur Molecular Genetics Berlin 4 Universtiy of Patras, School of Medicine

* Address correspondence to: E-mail: geodinos{at}med.upatras.gr

Abstract

New 16-membered 9-aryl-alkyl oxime derivatives of 5-O-mycaminosyl-tylonolid (OMT) have recently been prepared and found to exhibit high activity against macrolide resistant strains. Here, we show that these compounds do not affect the binding of tRNAs to ribosomes in a cell-free system derived from Escherichia coli, nor can they inhibit peptidytransferase, peptidyl-tRNA translocation or poly(U)-dependent poly(Phe) synthesis. However, they severely inhibit poly(A)-dependent poly(Lys) synthesis and compete with erythromycin or tylosin for binding to common or partially overlapping sites in the ribosome. According to footprinting analysis, the lactone ring of these compounds seems to occupy the classical binding site of macrolides that is located at the entrance of the exit tunnel, while the extending alkyl-aryl side chain appears to penetrate deeper in the tunnel where it protects nucleoside A752 in domain II of 23S rRNA. Additionally, this side chain causes an increased affinity for mutant ribosomes that may be responsible for their effectiveness against macrolide resistant strains. As revealed by detailed kinetic analysis, these compounds behave as slow-binding ligands interacting with functional ribosomal complexes through a one-step mechanism. This type of inhibitors has several attractive features and offers many chances in designing new potent drugs.


Key words: Structure/function/mechanism, Antibiotic mechanisms, Protein synthesis inhibitors


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[Abstract] [Full Text] [PDF]


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