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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate
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Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

机译：对vanA耐药菌株具有活性的万古霉素类似物可抑制细菌转糖基化酶而无需结合底物

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摘要

Bacterial transglycosylases are enzymes that couple the disaccha-ride subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopep-tides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBPIb, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.
机译：细菌转糖基化酶是将肽聚糖的二糖亚基偶联形成长碳水化合物链的酶。这些酶是五糖类抗生素莫能霉素的靶标，也是克服万古霉素耐药性的某些糖肽的靶标。由于细菌转糖基酶是难以研究的酶，因此以前无法评估莫能霉素如何抑制它们或确定糖肽类似物是否直接靶向它们。我们已经确定了能够对抑制剂进行动力学分析的转糖基化酶检测条件，并研究了莫能霉素以及各种糖肽对大肠杆菌青霉素结合蛋白1b（PBP1b）的抑制作用。我们报告说，无法结合底物的氯联苯万古霉素类似物仍然抑制大肠杆菌PBP1b，这表明这些化合物直接与酶相互作用。这些发现支持以下假设：氯联苯万古霉素衍生物通过靶向细菌转糖基糖苷酶来克服vanA耐药性。我们还发现，正如人们长期以来认为的那样，莫诺霉素相对于PBPIb的脂质II底物没有竞争性。随着评估细菌转糖基酶的合适方法的发展，现在有可能探究某些潜在的非常重要的抗生素的作用机理。

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