title: Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1.
abstract: There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2-fold were observed.
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia.
authors.forename: Omid Khalili
authors.initials: OK
authors.lastname: Arjomandi
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia; Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan, Egypt.
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Hussein
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Vella
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia.
authors.forename: Yusralina
authors.initials: Y
authors.lastname: Yusof
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, QLD, 4029, Australia.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Sidjabat
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schenk
authors.affiliation: The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia. Electronic address: r.mcgeary@uq.edu.au.
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007700:Kinetics; D007711:Klebsiella pneumoniae / Q000201:enzymology; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
keywords: Antibiotic resistance; Enzyme inhibitor; Metallo-β-lactamase