title: B1-Metallo-β-Lactamases: Where Do We Stand?
abstract: Metallo-β-Lactamases (MBLs) are class Bβ-lactamases that hydrolyze almost all clinically-availableβ-lactam antibiotics. MBLs feature the distinctive αβ/βα sandwich fold of the metallo-hydrolase/oxidoreductase superfamily and possess a shallow active-site groove containing one or two divalent zinc ions, flanked by flexible loops. According to sequence identity and zinc ion dependence, MBLs are classified into three subclasses (B1, B2 and B3), of which the B1 subclass enzymes have emerged as the most clinically significant. Differences among the active site architectures, the nature of zinc ligands, and the catalytic mechanisms have limited the development of a common inhibitor. In this review, we will describe the molecular epidemiology and structural studies of the most prominent representatives of class B1 MBLs (NDM-1, IMP-1 and VIM-2) and describe the implications for inhibitor design to counter this growing clinical threat.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Mojica
authors.affiliation: Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106, USA. robert.bonomo@va.gov.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin TX, 78712, USA. Walt.Fast@austin.utexas.edu.
authors.forename: Walter
authors.initials: W
authors.lastname: Fast
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism*; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001618:beta-Lactamases; D015032:Zinc