Exploring cell wall biosynthetic complexes for next generation antimicrobial discovery

细胞壁的生物合成是细菌新陈代谢的重要部分，也是许多抗菌剂的关键靶点。细菌细胞的细胞壁由一种被称为肽聚糖(PG)的糖基聚合物组成，它与多肽桥交联。这种结构对稳定细菌细胞包膜并保持细胞形状和完整性很重要。抗生素破坏PG结构或其前体，导致生长终止或细胞裂解。所有细菌细胞都依赖于一系列PG生物合成酶，这些酶与其他蛋白质形成复合体，进行生长和细胞分裂。在所有细菌中都产生了大量的青霉素结合蛋白，它们参与了细胞壁生物合成的不同方面。直到最近，人们还不知道为什么细胞中存在如此多的PBP蛋白，因为它们被认为都具有相同的功能。然而，人们发现，大多数针对PBPS的临床使用药物都针对B类单功能PBP酶。最近，人们发现这些PBPs与SEDS糖基转移酶形成相互依赖的复合体。在大肠杆菌中，有不同的SEDS-BPBP复合体参与细胞分裂(FtsW-PBP3)和细胞生长(RodA-PBP2)。对SEDS-BPBP之间相互作用机制的新理解表明，一个来自B类PBP的跨膜螺旋插入到SEDS蛋白的跨膜螺旋中，导致SEDS蛋白的构象变化，激活其糖基转移酶活性。这一新的理解非常重要，现在认为PG基质主要是由SEDS-PBP复合体与其他先前定义良好的A类PBP合成的，这些复合体执行与这些复合体相同的功能，修复孔洞并填充PG基质。这使得B类PBPs成为β-内酰胺类抗生素的一个非常可行的靶点，因为它们在细胞中的作用非常重要。

Cell wall biosynthesis is a vital part of bacterial metabolism and is a key target of many antimicrobials. The cell wall in bacterial cells consists of a sugar-based polymer known as peptidoglycan (PG) which is crosslinked with peptide bridges. This structure is important in stabilising the bacterial cell envelope and maintains cell shape and integrity. The disruption of PG structure or its precursors by antibiotics results in the termination of growth or cell lysis. All bacterial cells depend on a series of PG biosynthetic enzymes that work in complex with other proteins to carry out growth and cell division. In all bacterial species are a large number of penicillin binding proteins (PBPs) produced that are involved in different aspects of cell wall biosynthesis. Until recently it wasn't known why there were so many PBP proteins present in the cell as they were thought to all carry out the same function. However, it was discovered that most of the clinically used drugs that target PBPs target the class B monofunctional PBP enzymes. Recently, it was identified that these PBPs work in a co-dependent complex with SEDs glycosyltransferase enzymes. In E. coli there are separate SEDs-bPBP complexes involved in cell division (FtsW-PBP3) and cell growth (RodA-PBP2). A new understanding of the mechanism of interaction between the SEDs-bPBP has shown a single transmembrane helix from the class B PBP inserts into the transmembrane helices of the SEDs protein causing a conformational change in the SEDs protein, activating its glycosyltransferase activity.This new understanding is very important, it is now believed that the PG matrix is primarily synthesised by the SEDs-PBP complex with the other previously well-defined class A PBPs that carry out the same function as these complex thought to repair holes and fill in the PG matrix instead. This makes class B PBPs a very viable target to beta-lactam antibiotics as their role in the cell is very essential.