探究曲霉茉莉酸A与金属β-内酰胺酶NDM-1、VIM-2和IMP-7的相互作用
Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7.
作者信息
Bergstrom Alexander, Katko Andrew, Adkins Zach, Hill Jessica, Cheng Zishuo, Burnett Mia, Yang Hao, Aitha Mahesh, Mehaffey M Rachel, Brodbelt Jennifer S, Tehrani Kamaleddin H M E, Martin Nathaniel I, Bonomo Robert A, Page Richard C, Tierney David L, Fast Walter, Wright Gerard D, Crowder Michael W
机构信息
Department of Chemistry and Biochemistry, Miami University , 650 East High Street, Oxford, Ohio 45056, United States.
Department of Chemistry, University of Texas at Austin , Austin, Texas 78712, United States.
出版信息
ACS Infect Dis. 2018 Feb 9;4(2):135-145. doi: 10.1021/acsinfecdis.7b00106. Epub 2017 Nov 9.
Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.
金属β-内酰胺酶（MBLs）对β-内酰胺类抗生素的持续有效性构成了日益严重的威胁。最近，曲霉茉莉酸A（AMA）被鉴定为一种MBL抑制剂，但其抑制模式尚未完全明确。平衡透析和金属分析研究表明，当MBL处于微摩尔浓度时，2当量的AMA能有效地从MBL NDM-1、VIM-2和IMP-7中去除1当量的Zn(II)。相反，1H NMR研究表明，当MBL/AMA处于毫摩尔浓度时，2当量的AMA能从Co(II)取代的NDM-1、VIM-2和IMP-7中去除2当量的Co(II)。我们的研究结果表明，AMA通过去除临床上最重要的MBL中β-内酰胺水解所需的活性位点金属离子来抑制MBL。
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