Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-β-lactamase
Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-β-lactamase
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DOI：
10.1016/s1074-5521(98)90632-9
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发表时间：
1998-04-01
影响因子：
--
通讯作者：
Hammond, GG
中科院分区：
文献类型：
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作者：
Toney, JH;Fitzgerald, PMD;Hammond, GG
背景：脆弱类杆菌等革兰氏阴性菌对碳青霉烯类抗生素的高度耐药部分是由广谱金属β-内酰胺酶的表达引起的，该酶能将药物水解为非活性形式。耐药菌联合应用金属β-内酰胺酶抑制剂有望恢复碳青霉烯类抗生素的抗菌活性。结果：联苯四氮唑(BPTs)是一类有效的金属β-内酰胺酶竞争性抑制剂，经筛选鉴定，并利用酶结构的分子结构模型进行预测。结合在BPT L-159,061上的酶的X射线晶体结构表明，该缓蚀剂的四唑部分直接与活性中心的两个锌原子中的一个相互作用，取代了金属结合的水分子。结论：BPT抑制剂可使表达金属β-内酰胺酶的临床分离株对亚胺培南或青霉素G敏感，但对利福平无增敏作用。
Background: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems.Results: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis.Conclusions: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.