Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
J Enzyme Inhib Med Chem. 2013 Feb;28(1):137-42. doi: 10.3109/14756366.2011.640632. Epub 2012 Jan 11.
The increasing prevalence of drug resistant bacteria is a pandemic problem. Metallo-β-lactamases (MBLs) are one of the main causes of drug resistance due to hydrolysis of β-lactam antibiotics. Thus, the development of effective inhibitors of MBLs remains urgent. The compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-β-lactamase from Bacillus anthracis (Bla2), which causes anthrax. Kinetic evaluation with nitrocefin as a substrate indicates that thiomaltol inhibits Bla2 in a time-dependent manner with an IC(50) value of 290 µM after 20 min preincubation. Progress curve analysis and reversibility tests suggest that thiomaltol is a reversible, slow-binding inhibitor with a K(i) of 85 ± 30 µM. Furthermore, studies on the modality of inhibition and in silico analysis indicate thiomaltol to be a competitive inhibitor. The results demonstrate that thiomaltol is a promising lead compound for slow binding inhibitor design of Bla2.
耐药菌的不断增加是一个全球性的问题。金属β-内酰胺酶（MBLs）是导致β-内酰胺类抗生素水解的主要耐药原因之一。因此，开发有效的 MBLs 抑制剂仍然迫在眉睫。本研究以硫代麦芽糖为先导化合物，研究其抑制炭疽杆菌（Bla2）金属β-内酰胺酶的能力，Bla2 可导致炭疽病。以硝替头孢菌素作为底物进行动力学评估表明，硫代麦芽糖以时间依赖的方式抑制 Bla2，在 20 分钟预孵育后，IC（50）值为 290 µM。进展曲线分析和可逆性试验表明，硫代麦芽糖是一种具有 K（i）值为 85±30 µM 的可逆、慢结合抑制剂。此外，抑制方式的研究和计算分析表明硫代麦芽糖是一种竞争性抑制剂。结果表明，硫代麦芽糖是一种有前途的 Bla2 慢结合抑制剂设计的先导化合物。
