title: [Structure-Function Analysis and Development of Inhibitors of Metallo-β-lactamases Conferring Drug Resistance in Bacteria].
abstract: Metallo-β-lactamases (MBLs) are di-Zn(II) metalloenzymes that efficiently hydrolyze most β-lactam antibiotics used in clinical settings. Bacteria producing MBLs have been isolated from clinical settings and from natural environments such as rivers and soils, and are now recognized as a new potential threat to human health. No effective inhibitors are available for clinical use, making the treatment of infectious diseases caused by bacteria producing MBLs more difficult. IMP-1 is encoded on a plasmid which can be horizontally transferred between bacterial strains. Our studies on MBLs, and especially on IMP-1, focus on understanding the role of Zn(II) ion(s) in the hydrolysis of β-lactam antibiotics and on the detailed structure of the IMP-1 active site in order to develop efficient inhibitors. We investigated the role of the two Zn(II) ions in IMP-1 by kinetic, spectroscopic and thermodynamic analyses. The results revealed that the first Zn(II) ion is necessary for the hydrolysis of β-lactam antibiotics while the second Zn(II) ion enhances enzyme activity and structural stability, thus helping the enzyme achieve maximum activity. The detailed structures of the IMP-1 active site were examined by X-ray crystallography. Thiol compounds for irreversibly inhibiting IMP-1 were developed and the binding mode of these inhibitors was investigated in detail. These findings will aid the design of inhibitors that target MBLs.
authors.affiliation: Environmental Safety Center, Kumamoto University.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D015032:Zinc / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
chemical_list: D065093:beta-Lactamase Inhibitors; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases; D015032:Zinc