Award details

Regulation of Autolysins

Reference	BB/W013630/1
Principal Investigator / Supervisor	Professor Waldemar Vollmer
Co-Investigators / Co-Supervisors
Institution	Newcastle University
Department	Biosciences Institute
Funding type	Research
Value (£)	427,119
Status	Current
Type	Research Grant
Start date	01/07/2022
End date	30/06/2025
Duration	36 months

Abstract

The thin, mainly single layered peptidoglycan sacculus resides in the periplasm of diderm bacteria, protecting the cell from bursting due to its turgor and maintaining the shape of the cell. Growing and dividing bacteria enlarge the surface of their sacculus by the actions of peptidoglycan synthases and hydrolases. The latter are also called autolysis because they can cause lysis of the own cell under certain conditions, for example in the presence of antibiotics inhibiting peptidoglycan synthesis. Hence, the cell has to control the activities of the potentially dangerous autolysins during growth and cell division to prevent lysis and allow controlled expansion of the peptidoglycan layer. How peptidoglycan hydrolases are regulated in the periplasm of the model bacterium Escherichia coli is known only for few of the amidases active in daughter cell separation after cell division, but unknown for key classes of autolysins, the lytic transglycosylases and DD-endopeptidases. How these autolysins are regulated is the topic of this proposal. Based on our previous work and new preliminary data we hypothesise that peptidoglycan hydrolases are regulated by multiple protein-protein interactions. We now aim to determine the molecular details of interactions between different peptidoglycan hydrolases and between hydrolases and regulators, focusing on the soluble lytic transglycosylase Slt and DD-endopeptidases. We will also determine how these hydrolases are coordinated with peptidoglycan synthases, and how they become de-regulated when cells are exposed to an antibiotic that targets peptidoglycan biosynthesis. We expect that the project will provide molecular insights about how peptidoglycan hydrolases function in the cell. More broadly, the project will likely also unravel key aspects of the mechanism of peptidoglycan growth and reveal how antibiotics trigger cell lysis.

Summary

Bacteria are small, often around 1/1000 of a millimetre in size, and yet remarkably robust to be able to survive and propagate in different environments. Some bacteria can cause severe infections that need to be treated with antibiotics but many bacteria are beneficial to human health or play a major role in maintaining healthy ecosystems on the earth. One of the defining features of bacteria is their cell envelope which contains the cell wall made of peptidoglycan. Peptidoglycan forms a layer around the cell membrane to protect the cell from bursting due to its internal pressure of several atmospheres. A second major role of peptidoglycan is to maintain the specific shape (sphere, rod or other) of a bacterial cell. To fulfil these functions the peptidoglycan layer completely encases the cell membrane with a net-like structure, bearing much of the stress caused by the internal pressure. Some of our best antibiotics, for example Penicillin, inhibit the synthesis of peptidoglycan which indirectly causes defects in the layer followed by the disintegration (lysis) of the cell. In order to grow and divide, bacteria need to enlarge their stress-bearing peptidoglycan layer, which does not only require the the synthesis of new peptidoglycan and its attachment to the existing layer. Peptidoglycan hydrolases are also needed to open meshes in the net to allow the insertion of the new peptidoglycan and expand its surface. These hydrolases are also called autolysins because they are capable of causing the lysis of the own cell under certain conditions. The Gram-negative model bacterium Escherichia coli is known to have more than 20 autolysins, categorized in three major classes, but how their potentially dangerous activities are controlled in the cell is only poorly understood for some of them. This proposal aims to gain a molecular understanding of the regulation of key autolysins in the model bacterium and how they become deregulated in the presence of an antibiotic.

Committee	Research Committee B (Plants, microbes, food & sustainability)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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