Penicillin-binding proteins (PBPs) are the targets of the β-lactams, the most successful class of antibiotics ever developed against bacterial infections. Unfortunately, the worldwide and rapid spread of large spectrum β-lactam resistance genes such as carbapenemases is detrimental to the use of antibiotics in this class. New potent PBP inhibitors are needed, especially compounds that resist β-lactamase hydrolysis. Here we describe the structure of the E. coli PBP2 in its Apo form and upon its reaction with 2 diazabicyclo derivatives, avibactam and CPD4, a new potent PBP2 inhibitor. Examination of these structures shows that unlike avibactam, CPD4 can perform a hydrophobic stacking on Trp370 in the active site of E. coli PBP2. This result, together with sequence analysis, homology modeling, and SAR, allows us to propose CPD4 as potential starting scaffold to develop molecules active against a broad range of bacterial species at the top of the WHO priority list.

中文翻译：

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大肠杆菌青霉素结合蛋白（PBP）2抑制的结构基础，药物设计的平台。

青霉素结合蛋白（PBP）是β-内酰胺的靶标，β-内酰胺是针对细菌感染开发的最成功的一类抗生素。不幸的是，诸如β-碳青霉烯酶的大范围β-内酰胺抗性基因在世界范围内的迅速传播不利于此类抗生素的使用。需要新的有效PBP抑制剂，尤其是能抵抗β-内酰胺酶水解的化合物。在这里，我们描述了Apo形式的大肠杆菌PBP2的结构，以及它与2个二氮杂双环衍生物，avibactam和CPD4（一种新的有效PBP2抑制剂）反应后的结构。这些结构的检查表明，与avibactam不同，CPD4可以在大肠杆菌PBP2的活性位点的Trp370上进行疏水性堆积。该结果与序列分析，同源性建模和SAR一起，