Exploring cell wall biosynthetic complexes for next generation antimicrobial discovery

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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.