Kinetic characterization of a slow-binding inhibitor of Bla2: thiomaltol

摘要

The increasing prevalence of drug resistant bacteria is a pandemic problem. Metallo-beta-lactamases (MBLs) are one of the main causes of drug resistance due to hydrolysis of (3-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-beta-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 IC50 value of 290 mM after 20 min preincubation. Progress curve analysis and reversibility tests suggest that thiomaltol is a reversible, slow-binding inhibitor with a K of 85(+-)30 u.M. 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.