Non-classical transpeptidases yield insight into new antibacterials.
Non-classical transpeptidases yield insight into new antibacterials.
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DOI：
10.1038/nchembio.2237
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发表时间：
2017-01
影响因子：
14.8
通讯作者：
Lamichhane G
中科院分区：
文献类型：
--
作者：
Kumar P;Kaushik A;Lloyd EP;Li SG;Mattoo R;Ammerman NC;Bell DT;Perryman AL;Zandi TA;Ekins S;Ginell SL;Townsend CA;Freundlich JS;Lamichhane G
细菌的生存需要一个完整的肽聚糖层，一个包裹细胞质膜的三维外骨骼。历史上，已知肽聚糖合成的最后步骤由d，d-转肽酶进行，所述转肽酶是被β-内酰胺抑制的酶，所述β-内酰胺构成临床使用的所有抗菌剂的>50%。在这里，我们表明β-内酰胺类的碳青霉烯亚类是明显有效的，不仅因为它们抑制d，d-转肽酶并且是β-内酰胺酶的不良底物，而且主要是因为它们还抑制非经典转肽酶，即l，d-转肽酶，其在分枝杆菌的肽聚糖中产生大部分键。我们已经表征了负责抑制M的l，d-转肽酶的分子机制。结核病和一系列细菌，包括ESKAPE病原体，并利用这些信息来设计，合成和测试具有强效抗菌活性的简化碳青霉烯类。
Bacterial survival requires an intact peptidoglycan layer, a 3-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by d,d-transpeptidases, enzymes that are inhibited by the β-lactams which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of β-lactams is distinctly effective not only because they inhibit d,d-transpeptidases and are poor substrates for β-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the l,d-transpeptidases, that generate the majority of linkages in the peptidoglycan of mycobacteria. We have characterized the molecular mechanisms responsible for inhibition of l,d-transpeptidases of M. tuberculosis and a range of bacteria, including ESKAPE pathogens, and utilized this information to design, synthesize and test simplified carbapenems with potent antibacterial activity.