title: Inhibitor discovery of full-length New Delhi metallo-β-lactamase-1 (NDM-1).
abstract: New Delhi metallo-β-lactmase-1 (NDM-1) has recently attracted extensive attention for its biological activities to catalyze the hydrolysis of almost all of β-lactam antibiotics. To study the catalytic property of NDM-1, the steady-kinetic parameters of NDM-1 toward several kinds of β-lactam antibiotics have been detected. It could effectively hydrolyze most β-lactams (k cat/K m ratios between 0.03 to 1.28 µmol⁻¹.s⁻¹), except aztreonam. We also found that thiophene-carboxylic acid derivatives could inhibit NDM-1 and have shown synergistic antibacterial activity in combination with meropenem. Flexible docking and quantum mechanics (QM) study revealed electrostatic interactions between the sulfur atom of thiophene-carboxylic acid derivatives and the zinc ion of NDM-1, along with hydrogen bond between inhibitor and His189 of NDM-1. The interaction models proposed here can be used in rational design of NDM-1 inhibitors.
authors.affiliation: State Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, Nanjing, Jiangsu, China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Shen
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Xingzhen
authors.initials: X
authors.lastname: Lao
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Fang
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Jiao
authors.initials: J
authors.lastname: Chen
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001398:Aztreonam / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D006868:Hydrolysis; D007700:Kinetics; D000077731:Meropenem; D062105:Molecular Docking Simulation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D013845:Thienamycins / Q000737:chemistry* / Q000494:pharmacology; D018440:beta-Lactam Resistance / Q000187:drug effects; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics; D047090:beta-Lactams / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem; D001398:Aztreonam