title: Kinetic characterization of a slow-binding inhibitor of Bla2: thiomaltol.
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 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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Schlesinger
authors.forename: Britain
authors.initials: B
authors.lastname: Bruner
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Farmer
authors.forename: Sung-Kun
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000201:enzymology*; D002511:Cephalosporins / Q000378:metabolism; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: C583493:3-hydroxy-2-methyl-4H-pyran-4-thione; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D011714:Pyrans; D013871:Thiones; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; C021720:nitrocefin