Development of irreversible inhibitors forβ-lactam inactived enzyme, metallo-β-lactamase

β-内酰胺失活酶、金属-β-内酰胺酶不可逆抑制剂的开发

• 批准号: 21590116
• 负责人: KUROSAKI Hiromasa
• 金额: $ 3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590116/
• 关键词: 医薬分子設計; 感染症; β-ラクタム剤; 薬剤耐性菌; 阻害剤; 金属酵素; 薬学; 抗生物質; 耐性菌; 細菌; 酵素

IMP-1 metallo-β-lactamase is a dinuclear Zn(II) enzyme that catalyzes the hydrolysis and inactivation of mostβ-lactams including carbapenems, and is involved in one of the mechanisms for generating clinical resistance to antibiotics in pathogenic bacteria. We investigated the metal preferences of Zn(II) and Co(II) for the apo-enzyme of IMP-1 metallo-β-lactamase, apo-IMP-1, which contains a dinuclear metal binding site(the Zn1 and Zn2 sites), by UV-visible spectroscopy. The UV-visible spectrum of apo-IMP-1 containing 1 equiv. of Co(II) and 1 equiv. of Zn(II) showed a high preference of Zn(II) for the Zn1 site compared to Co(II). The interaction of IMP-1 metallo-β-lactamase with mercaptoacetic acid was also investigated using Co(II)-substituted IMP-1 and UV-visible spectroscopy. Possible metal binding modes of Co(II) or Zn(II) to the dinucelar metal binding site in apo-IMP-1 and of mercaptoacetic acid to Co(II)-substituted IMP-1 are proposed.

IMP-1金属β-内酰胺酶是一种双核Zn（II）酶，可催化包括碳青霉烯类在内的大多数β-内酰胺类酶的水解和失活，参与致病菌临床产生抗生素耐药的机制之一。我们利用紫外可见光谱研究了锌（II）和钴（II）对含有双核金属结合位点（Zn1和Zn2位点）的载脂蛋白-IMP-1金属β-内酰胺酶载脂蛋白-1的金属偏好。含有1等量Co（II）和1等量Zn（II）的apo-IMP-1的紫外可见光谱显示，与Co（II）相比，Zn（II）对Zn1位点有较高的偏好。利用Co（II）取代的IMP-1和紫外可见光谱研究了IMP-1金属β-内酰胺酶与巯基乙酸的相互作用。提出了Co（II）或Zn（II）与载脂蛋白-IMP-1中双核金属结合位点和巯基乙酸与Co（II）取代的IMP-1的可能金属结合模式。

项目成果

A demetallation method for IMP-1 metallo-ss-lactamase with restored enzymatic activity upon addition of metal ion(s)

IMP-1 金属-β-内酰胺酶的脱金属方法，添加金属离子后酶活性恢复

• DOI: 10.1002/cbic.201100342
• 发表时间: 2011
• 期刊: ChemBioChem
• 影响因子: 3.2
• 作者: Yamaguchi Y;Ding S;Murakami E;Imamura K;Fuchigami S;Hashiguchi R;Yutani K;Mori H;Suzuki S;Arakawa Y;Kurosaki H
• 通讯作者: Kurosaki H

Detection of metallo-β-lactamase producing bacteria by fluoresent probe having dansyl and thiol groups

用具有丹酰基和硫醇基团的荧光探针检测产金属-β-内酰胺酶细菌

• 发表时间: 2010
• 作者: Kouki Matsuda;Yoshihiro Yamaguchi;Junzo Hirose;Yoshichika Arakawa;Hiromasa Kurosaki
• 通讯作者: Hiromasa Kurosaki

etection of metallo-β-lactamase producing bacteria by fluorescent probe having dansyl and thiol groups

具有丹酰基和硫醇基团的荧光探针对产生金属-β-内酰胺酶的细菌的影响

• 发表时间: 2010
• 作者: Koki MATSUDA;Yoshihiro YAMAGUCHI;Junzo HIROSE;Yoshichika ARAKAWA;Hiromasa KUROSAKI
• 通讯作者: Hiromasa KUROSAKI

A demetallation method for IMP-1 metallo-β-lactamase that restored enzymatic activity upon addition of metal ion(s)

IMP-1 金属-β-内酰胺酶的脱金属方法，在添加金属离子后恢复酶活性

• 发表时间: 2011
• 期刊: ChemBioChem
• 影响因子: 3.2
• 作者: Yoshihiro Yamaguchi;Shijia Ding;Emi Murakami;Kayo Imamura;Sachiko Fuchigami;Ryo Hashiguchi;Katsuhide Yutani;Hiromasa Mori;Shinnichiro Suzuki;Yoshichika Arakawa;Hiromasa Kurosaki
• 通讯作者: Hiromasa Kurosaki

Metal preference of Zn(II) and Co(II) for the dinuclear metal binding site of IMP-1 metallo-β-lactamase and spectroscopic properties of Co(II)-substituted IMP-1 with mercaptoacetic acid

Zn(II) 和 Co(II) 对 IMP-1 金属-β-内酰胺酶双核金属结合位点的金属偏好以及 Co(II) 取代的 IMP-1 与巯基乙酸的光谱特性

• 发表时间: 2011
• 期刊: Med. Chem. Commun
• 作者: Yoshihiro Yamaguchi;Kayo Imamura;Ako Sasao;Emi Murakami;Yoshichika Arakawa;Hiromasa Kurosaki
• 通讯作者: Hiromasa Kurosaki