Exploring cell wall biosynthetic complexes for next generation antimicrobial discovery

探索细胞壁生物合成复合物以发现下一代抗菌剂

• 批准号: 2391884
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2391884
• 关键词: Exploring; cell; wall; biosynthetic; complexes

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.

细胞壁生物合成是细菌代谢的重要组成部分，并且是许多抗菌剂的关键靶标。细菌细胞中的细胞壁由称为肽聚糖（PG）的糖基聚合物组成，其与肽桥交联。这种结构在稳定细菌细胞包膜和保持细胞形状和完整性方面很重要。抗生素对PG结构或其前体的破坏导致生长终止或细胞裂解。所有的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一起进行生长和细胞分裂。在所有的细菌物种中，都产生大量的青霉素结合蛋白（PBP），它们参与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，发现大多数临床使用的靶向PBP的药物靶向B类单功能PBP酶。最近，它被确定，这些PBPs与SED糖基转移酶的共依赖复合物的工作。在大肠在大肠杆菌中，存在参与细胞分裂（FtsW-PBP 3）和细胞生长（RodA-PBP 2）的单独的SEDs-bPBP复合物。对SEDs-bPBP相互作用机制的新认识表明，来自B类PBP的单个跨膜螺旋插入到SEDs蛋白的跨膜螺旋中，引起SEDs蛋白的构象变化，激活其糖基转移酶活性。现在认为PG基质主要由SEDs-PBP复合物与其它先前良好合成的-定义了A类PBPs，它们执行与这些复合物相同的功能，被认为是修复孔并填充PG基质。这使得B类PBPs成为β-内酰胺抗生素的一个非常可行的靶标，因为它们在细胞中的作用非常重要。