Issue 3, 2012

Unprecedented inhibition of resistant penicillin bindingproteins by bis-2-oxoazetidinylmacrocycles

Abstract

Since the discovery of penicillin, bacteria have counteracted the action of antibiotics leading to a worrisome situation about antibiotic efficiency. During our research on non-traditional 1,3-bridged β-lactams embedded into macrocycles as potential inhibitors of Penicillin BindingProteins (PBPs), we unexpectedly synthesized bis-2-oxoazetidinylmacrocycles arising from a dimerization reaction under ring closing metathesis (RCM) conditions. These molecules were revealed to be good inhibitors of the D,D-peptidase from ActinomaduraR39, which is commonly used as a model of PBPs. To pursue the research on this type of novel compounds, a complete family of cyclodimers 4 and 5 was synthesized and evaluated against R39, and high molecular weight D,D-peptidases: PBP2a of methicillin-resistant Staphylococcus aureus and PBP5 of resistant Enterococcus faecium. Some bis-2-oxoazetidinylmacrocycles exhibited very promising activities against PBP2a. In order to explain the biological results, docking experiments of one cyclodimer (5e) into the R39 and PBP2a crystallographic structures were performed. The 3D structures of all the dimers were studied by quantum chemistry calculations and the reactivity of one cyclodimer (5e) was evaluated using an elaborate model of the R39 active site. Our results highlighted that the activity of the compounds is most probably related to their conformational adaptability, depending on the size of the macrocycles and the geometrical constraints induced by intramolecular H bonds.

Graphical abstract: Unprecedented inhibition of resistant penicillin binding proteins by bis-2-oxoazetidinylmacrocycles

Supplementary files

Article information

Article type
Concise Article
Submitted
04 Oct 2011
Accepted
25 Nov 2011
First published
15 Dec 2011

Med. Chem. Commun., 2012,3, 344-351

Unprecedented inhibition of resistant penicillin bindingproteins by bis-2-oxoazetidinylmacrocycles

A. Sliwa, G. Dive, A. Zervosen, O. Verlaine, E. Sauvage and J. Marchand-Brynaert, Med. Chem. Commun., 2012, 3, 344 DOI: 10.1039/C2MD00251E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements