Department of Pharmaceutical Chemistry, University of California San Francisco , 600 16th Street San Francisco, California 94143-2240, United States.
J Med Chem. 2014 Jun 26;57(12):5449-58. doi: 10.1021/jm5006572. Epub 2014 Jun 16.
Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-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-β-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.
β-内酰胺酶（BLs）的产生是细菌对抗β-内酰胺类抗生素的最广泛的耐药机制。BLs 的底物谱已变得越来越广泛，构成了严重的健康问题。因此，迫切需要新型 BL 抑制剂。硼酸过渡态类似物能够逆转 A 类和 C 类 BLs 赋予的耐药性。我们描述了一种硼酸类似物，对 A 类和 C 类基于丝氨酸的 BLs 具有有趣且强效的广谱活性。从苯并（b）噻吩-2-硼酸（BZBTH2B）开始，它是一种纳摩尔非β-内酰胺抑制剂，可增强第三代头孢菌素对产 AmpC 耐药菌的活性，我们设计了一种新型广谱纳摩尔抑制剂，用于 A 类和 C 类 BLs。讨论了基于结构的药物设计（SBDD）、合成、酶学数据和 X 射线晶体学结果。我们通过双突变体热力学循环研究阐明了负责与丝氨酸活性 BLs 产生广谱活性的抑制剂结合几何形状。
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