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Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acsinfecdis.7b00106 Alexander Bergstrom 1 , Andrew Katko 1 , Zach Adkins 1 , Jessica Hill 1 , Zishuo Cheng 1 , Mia Burnett 1 , Hao Yang 1 , Mahesh Aitha 1 , M Rachel Mehaffey 2 , Jennifer S Brodbelt 2 , Kamaleddin H M E Tehrani 3 , Nathaniel I Martin 3 , Robert A Bonomo 4 , Richard C Page 1 , David L Tierney 1 , Walter Fast 5 , Gerard D Wright 6 , Michael W Crowder 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acsinfecdis.7b00106 Alexander Bergstrom 1 , Andrew Katko 1 , Zach Adkins 1 , Jessica Hill 1 , Zishuo Cheng 1 , Mia Burnett 1 , Hao Yang 1 , Mahesh Aitha 1 , M Rachel Mehaffey 2 , Jennifer S Brodbelt 2 , Kamaleddin H M E Tehrani 3 , Nathaniel I Martin 3 , Robert A Bonomo 4 , Richard C Page 1 , David L Tierney 1 , Walter Fast 5 , Gerard D Wright 6 , Michael W Crowder 1
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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, 1H 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.
中文翻译：
探索曲霉花生胺A与金属β-内酰胺酶NDM-1，VIM-2和IMP-7的相互作用
金属β-内酰胺酶（MBL）对β-内酰胺抗生素的持续疗效构成越来越大的威胁。最近，曲霉芦荟胺A（AMA）被鉴定为MBL抑制剂，但其抑制方式尚未完全表征。平衡透析和金属分析研究表明，当MBL处于微摩尔浓度时，当量2 AMA可以有效地从MBL NDM-1，VIM-2和IMP-7中去除1 eq的Zn（II）。相反，1 H NMR研究表明，当MBL / AMA浓度为毫摩尔时，2当量的AMA从Co（II）取代的NDM-1，VIM-2和IMP-7中除去了2当量的Co（II）。我们的发现表明，AMA通过去除最具有临床意义的MBL中的β-内酰胺水解所需的活性位点金属离子来抑制MBL。
更新日期：2017-11-09
中文翻译：
探索曲霉花生胺A与金属β-内酰胺酶NDM-1，VIM-2和IMP-7的相互作用
金属β-内酰胺酶（MBL）对β-内酰胺抗生素的持续疗效构成越来越大的威胁。最近，曲霉芦荟胺A（AMA）被鉴定为MBL抑制剂，但其抑制方式尚未完全表征。平衡透析和金属分析研究表明，当MBL处于微摩尔浓度时，当量2 AMA可以有效地从MBL NDM-1，VIM-2和IMP-7中去除1 eq的Zn（II）。相反，1 H NMR研究表明，当MBL / AMA浓度为毫摩尔时，2当量的AMA从Co（II）取代的NDM-1，VIM-2和IMP-7中除去了2当量的Co（II）。我们的发现表明，AMA通过去除最具有临床意义的MBL中的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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