Targeting Class A and C Serine 尾-Lactamases with a Broad-Spectrum Boronic Acid Derivative

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• 作者：Donatella Tondi ; Alberto Venturelli ; Richard Bonnet ; Cecilia Pozzi ; Brian K. Shoichet ; Maria Paola Costi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5449-5458
• 全文大小：460K
• ISSN：1520-4804

文摘

Production of 尾-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight 尾-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-尾-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.