Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP-7

被引：51

作者：

Bergstrom, Alexander ^{[1
]}

Katko, Andrew ^{[1
]}

Adkins, Zach ^{[1
]}

Hill, Jessica ^{[1
]}

Cheng, Zishuo ^{[1
]}

Burnett, Mia ^{[1
]}

Yang, Hao ^{[1
]}

Aitha, Mahesh ^{[1
]}

Mehaffey, M. Rachel ^{[2
]}

Brodbelt, Jennifer S. ^{[2
]}

Tehrani, Kamaleddin H. M. E. ^{[3
]}

Martin, Nathaniel I. ^{[3
]}

Bonomo, Robert A. ^{[4
]}

Page, Richard C. ^{[1
]}

Tierney, David L. ^{[1
]}

Fast, Walter ^{[5
]}

Wright, Gerard D. ^{[6
,7
]}

Crowder, Michael W. ^{[1
]}

机构：

[1] Miami Univ, Dept Chem & Biochem, 650 East High St, Oxford, OH 45056 USA

[2] Univ Texas Austin, Dept Chem, Austin, TX 78712 USA

[3] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Chem Biol & Drug Discovery, Univ Weg 99, NL-3584 CG Utrecht, Netherlands

[4] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, Res Serv, 10701 East Blvd, Cleveland, OH USA

[5] Univ Texas Austin, Coll Pharm, Div Chem Biol & Med Chem, 107 W Dean Keeton, Austin, TX 78712 USA

[6] McMaster Univ, Michael G DeGroote Inst Infect Dis, 1280 Main St West, Hamilton, ON L8S 4L8, Canada

[7] McMaster Univ, Dept Biochem & Biomed Sci, 1280 Main St West, Hamilton, ON L8S 4L8, Canada

来源：

ACS INFECTIOUS DISEASES | 2018年 / 4卷 / 02期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

aspergillomarasmine A; metallo-beta-lactamase; NDM-1; VIM-2; IMP-7; antibiotic resistance; SPECTROSCOPIC CHARACTERIZATION; ANTIBIOTIC-RESISTANCE; MOLECULAR-MECHANISMS; MULTIDRUG-RESISTANT; STRUCTURAL BASIS; ACTIVE-SITE; INHIBITORS; NMR; COORDINATION; COBALT(II);

D O I：

10.1021/acsinfecdis.7b00106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Metallo-beta-lactamases (MBLs) are a growing threat to the continued efficacy of beta-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-1 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 beta-lactam hydrolysis among the most clinically significant MBLs.

引用

页码：135 / 145

页数：11

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