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

Author： Schlesinger Sara R.   Bruner Britain   Farmer Patrick J.   Kim Sung-Kun  

Publisher： Informa Healthcare

ISSN： 1475-6366

Source： Journal of Enzyme Inhibition and Medicinal Chemistry, Vol.28, Iss.1, 2013-02, pp. : 137-142

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Abstract

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 IC50 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 Ki 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.

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