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首页> 外文期刊>Biochemistry >Irreversible inhibition of the mycobacterium tuberculosis beta-lactarnase by clavulanate
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Irreversible inhibition of the mycobacterium tuberculosis beta-lactarnase by clavulanate

机译：克拉维酸对结核分枝杆菌β-内酰胺酶的不可逆抑制作用

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摘要

Members of the P-lactam class of antibiotics, which inhibit the bacterial D,D-transpeptidases involved in cell wall biosynthesis, have never been used systematically in the treatment of Mycobacterium tuberculosis infections because of this organism's resistance to beta-lactams. The critical resistance factor is the constitutive production of a chromosomally encoded, Ambler class A P-lactamase, BlaC in M. tuberculosis. We show that BlaC is an extended spectrum P-lactamase (ESBL) with high levels of penicillinase and cephalosporinase activity as well as measurable activity with carbapenems, including imipenem and meropenem. We have characterized the enzyme's inhibition by three FDA-approved beta-lactamase inhibitors: sulbactam, tazobactam, and clavulanate. Sulbactarn inhibits the enzyme competitively and reversibly with respect to nitrocefin. Tazobactam inhibits the enzyme in a time-dependent manner, but the activity of the enzyme reappears due to the slow hydrolysis of the covalently acylated enzyme. In contrast, clavulanate reacts with the enzyme quickly to form hydrolytically stable, inactive forms of the enzyme that have been characterized by mass spectrometry. Clavulanate has potential to be used in combination with approved P-lactam antibiotics to treat multi-drug resistant (MDR) and extremely drug resistant (XDR) strains of M. tuberculosis.
机译：P-内酰胺类抗生素的成员能够抑制参与细胞壁生物合成的细菌D，D-转肽酶，但由于该生物体对β-内酰胺类有抗性，因此从未被系统地用于治疗结核分枝杆菌感染。关键抗性因子是结核分枝杆菌中染色体编码的Ambler A类β-内酰胺酶BlaC的组成型产生。我们显示，BlaC是具有高水平的青霉素酶和头孢菌素酶活性以及与碳青霉烯类（包括亚胺培南和美洛培南）可测量的活性的广谱P-内酰胺酶（ESBL）。我们已经表征了三种FDA批准的β-内酰胺酶抑制剂对酶的抑制作用：舒巴坦，他唑巴坦和克拉维酸盐。 Sulbactarn相对于硝基cefin具有竞争性和可逆性抑制酶。他唑巴坦以时间依赖性方式抑制该酶，但是由于共价酰化酶的缓慢水解，该酶的活性重新出现。相反，棒酸与该酶快速反应，形成了水解稳定的，无活性的酶形式，该酶已通过质谱法进行了表征。克拉维酸盐有可能与批准的P-内酰胺类抗生素联合使用，以治疗结核分枝杆菌的多药耐药（MDR）和极耐药（XDR）菌株。

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