title: Inhibition of IMP-1 metallo-beta-lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives.
abstract: IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzyme found in some clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significantly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit purified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrolysis products which themselves were reversible competitive inhibitors. The thioesters also increased sensitivity to the carbapenem L-742,728 in an IMP-1-producing laboratory stain of Escherichia coli, but will need further modification to improve their activity in less permeable organisms such as Pseudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer an encouraging start to overcoming metallo-beta-lactamase-mediated resistance in bacteria.
authors.affiliation: Department of Biochemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Hammond
authors.forename: J L
authors.initials: JL
authors.lastname: Huber
authors.forename: M L
authors.initials: ML
authors.lastname: Greenlee
authors.forename: J B
authors.initials: JB
authors.lastname: Laub
authors.forename: K
authors.initials: K
authors.lastname: Young
authors.forename: L L
authors.initials: LL
authors.lastname: Silver
authors.forename: J M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: K D
authors.initials: KD
authors.lastname: Pryor
authors.forename: J K
authors.initials: JK
authors.lastname: Wu
authors.forename: B
authors.initials: B
authors.lastname: Leiting
authors.forename: D L
authors.initials: DL
authors.lastname: Pompliano
authors.forename: J H
authors.initials: JH
authors.lastname: Toney
mesh_terms: D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D015780:Carbapenems / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
chemical_list: D015780:Carbapenems; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors