title: A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1.
abstract: New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.
authors: Department of Chemistry, Fuzhou University, Fujian, China.
authors: Kongkai
authors: K
authors: Zhu
authors: Junyan
authors: J
authors: Lu
authors: Zhongjie
authors: Z
authors: Liang
authors: Xiangqian
authors: X
authors: Kong
authors: Fei
authors: F
authors: Ye
authors: Lu
authors: L
authors: Jin
authors: Heji
authors: H
authors: Geng
authors: Yong
authors: Y
authors: Chen
authors: Mingyue
authors: M
authors: Zheng
authors: Hualiang
authors: H
authors: Jiang
authors: Jun-Qian
authors: JQ
authors: Li
authors: Cheng
authors: C
authors: Luo
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D006801:Humans; D006868:Hydrolysis; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D000077731:Meropenem; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013845:Thienamycins / Q000378:metabolism*; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem