New Drug for Treatment of Chronic Bacterial Infection

描述(由申请人提供) 摘要：这项提议的目的是研究和利用细菌的肽聚糖层中存在的非经典交叉连接。这一层对细菌的生存至关重要，并通过连接多肽和糖链来维持。人类临床使用中最成功的抗生素之一，即内酰胺类和头孢菌素类，针对的是经典的4？3联系。现有的范例将肽聚糖层描述为一种主要由经典的4？3连接所维持的结构。我们最近对人类最重要的病原体之一结核分枝杆菌(Mtb)的研究表明，它的肽聚糖层由3？3(非经典交联物)组成，当细菌从一个生长阶段过渡到另一个生长阶段时，它会经历重塑。其他实验室最近在大肠杆菌和枯草杆菌等细菌中发现了这种酶，这表明这种酶广泛存在，对细菌的生存至关重要。最近发表的新证据表明，在慢性感染阶段，肽聚糖的重塑含有3？3个转肽键，与适应有关。在短短2年的时间里，我们已经鉴定了一个3？3转肽酶，现在已经解决了含有天然底物的晶体的分子结构。这项提议旨在开发和鉴定模拟底物抑制这种新型转肽酶活性的小分子。该抑制剂有望成为一种很有前途的新型抗菌药物。

DESCRIPTION (Provided by the applicant) Abstract: The aim of this proposal is to study and exploit the non-classical cross-linkages present in the peptidoglycan layer of bacteria. This layer is vital to the survival of bacilli and is maintained by linking peptide and glycan chains. One the most successful class of antibiotics in human clinical use, namely the ¿-lactams and cephalosporins, targets the classical 4?3 linkages. The existing paradigm describes the peptidoglycan layer as a structure largely maintained by classical 4?3 linkages. Our recent studies of one of the most significant human pathogens, Mycobacterium tuberculosis (Mtb), has revealed that its peptidoglycan layer is composed of 3?3 (non-classical cross-links) and undergoes remodeling when the bacterium transitions from one growth phase to another. Other laboratories have recently identified this enzyme in bacteria such as E. coli and B. subtilis suggesting that this enzyme is widely present and vital for viability of bacteria. Emerging evidence from recent publications link remodeling of the peptidoglycan to contain 3?3 transpeptide bonds to adaptation during chronic phase of infection. In a short period of 2 years we have characterized a 3?3 transpeptidase and have now solved the molecular structure of the crystal containing native substrate. This proposal aims to develop and identify small molecules that mimic the substrate inhibit this novel transpeptidase activity. The inhibitor would be a promising new class of antibacterial drug