Irreversible inhibition of metallo-β-lactamase (IMP-1) by 3-(3-mercaptopropionylsulfanyl)propionic acid pentafluorophenyl ester
Irreversible inhibition of metallo-β-lactamase (IMP-1) by 3-(3-mercaptopropionylsulfanyl)propionic acid pentafluorophenyl ester
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DOI：
10.1002/anie.200500835
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Goto, M
中科院分区：
文献类型：
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作者：
Kurosaki, H;Yamaguchi, Y;Goto, M
产生金属-β-内酰胺酶(MBLS)的病原菌正成为医学界面临的新挑战。这些酶催化广泛的β-内酰胺类抗生素的水解，包括亚胺培南等碳青霉烯类，其中一些编码在可转移的质粒中。[1，2]在目前已知的MBLS中，IMP-1是B1亚类的成员，由整合子结构中包含的blaIMP基因编码，[2，3]通过简单的水平基因转移到其他细菌中迅速传播。[4]此外，目前使用的许多丝氨酸b-内酰胺酶抑制剂，如克拉维酸、舒巴坦和三唑巴坦对MBLS无效。因此，MBLS抑制剂的开发对于这种广泛使用的β-内酰胺类抗生素的继续应用非常重要。到目前为止，已经报道了几种这样的抑制剂；[5-11]例如，Payne等人。证明了，在有氧条件下，硫代乙酸硫醇酯被MBLS(b-内酰胺酶II、CFIA和CPHA)水解后，通过与活性部位半胱氨酸残基形成二硫键而不可逆地结合到酶上。
Pathogenic bacteria that produce metallo-b-lactamases (MBLs) are emerging as a new challenge to the medical community. These enzymes catalyze the hydrolysis of a wide spectrum of b-lactams, including carbapenems such as imipenem, some of which are coded in transferable plasmids.[1, 2] Among the currently known MBLs, IMP-1, a member of subclass B1, which is encoded by the blaIMP gene included in the integron structure,[2, 3] rapidly spreads by facile horizontal gene transfer to other bacteria.[4] Moreover, many of the currently used serine b-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are ineffective against MBLs. Thus, the development of inhibitors of MBLs is important for the continuing application of such widely prescribed b-lactam antibiotics. Several such inhibitors have been reported to date;[5–11] for example, Payne et al. demonstrated [6] that mercaptoacetic acid, a hydrolysis product of mercaptoacetic acid thiol esters that are hydrolyzed by MBLs (b-lactamase II, CfiA, and CphA), binds irreversibly to the enzyme through formation of a disulfide bond with the active site cysteine residue under aerobic conditions, as evidenced