Synthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C

Bioorganic & Medicinal Chemistry
Astrid ZervosenAndré Luxen

Abstract

In response to the widespread use of β-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent β-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC(50): 1.3 μM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC(50) = 26 μM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC(50) = 138 μM) and a class C PBP (R39 from Actinomadura sp., IC(50) = 0.6 μM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species.

Citations

Jan 17, 2014·Journal of Chemical Biology·Gillian F WhyteRudiger Woscholski
Apr 27, 2013·Future Medicinal Chemistry·Bhaskar C DasTodd Evans
Dec 21, 2012·Expert Opinion on Drug Discovery·Stephen P East, Lynn L Silver
Jan 3, 2013·Annals of the New York Academy of Sciences·Lynn L Silver
Dec 3, 2014·Current Opinion in Pharmacology·Jean-Marie Frère, Malcolm G P Page
Oct 26, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Astrid ZervosenAndré Luxen
Feb 9, 2016·Chemical Society Reviews·Patricia AndrésCarlos Cativiela
Oct 5, 2013·Clinical Microbiology Reviews·Michael J Pucci, Karen Bush

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