Unprecedented inhibition of resistant penicillin binding proteins by bis-2-oxoazetidinyl macrocycles
(2012) MedChemComm — Vol. 3, n° 3, p. 344-351 (2012)
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- 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 Binding Proteins (PBPs), we unexpectedly synthesized bis-2-oxoazetidinyl macrocycles 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 Actinomadura R39, 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-oxoazetidinyl macrocycles 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. © 2012 The Royal Society of Chemistry.
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Sliwa, A., Dive, G., Zervosen, A., Verlaine, O., Sauvage, E., & Marchand-Brynaert, J. (2012). Unprecedented inhibition of resistant penicillin binding proteins by bis-2-oxoazetidinyl macrocycles. MedChemComm, 3(3), 344-351. https://doi.org/10.1039/c2md00251e (Original work published 2012)