The bacterial cell wall must be constantly renewed in order to grow and divide. This involves close coordination of lytic enzymes and peptidoglycan synthesis. In their study published in Communication in Nature, researchers led by Martin Thanbichler have now found that a central regulator can control completely different types of autolysins. Since many antibiotics target the bacterial cell wall, these findings may contribute to the development of new treatment methods against bacterial infections.
During evolution, cells have developed a wide range of strategies to stabilize their envelope against internal osmotic pressure, thus allowing them to grow in a variety of different environments.
Most bacterial species synthesize a semi-rigid cell wall surrounding the cytoplasmic membrane, whose main component, peptidoglycan, forms a dense meshwork surrounding the cell. In addition to its protective role, the cell wall also serves as a means of generating specific cell shapes, such as spheres, rods, or spirals, thus facilitating movement, surface colonization, and pathogenicity.
The presence of a cell wall presents its own challenges: cells must constantly renew it to grow and divide. To do this, they had to carefully create tears in the wall to allow it to expand and change, while quickly repairing the gaps with new material to prevent it from collapsing.
This cell wall remodeling process involves the cleavage of bonds by lytic enzymes, also known as autolysins, and the subsequent insertion of new cell wall material by peptidoglycan synthases. The activities of these two antagonistic groups of proteins must be closely coordinated to prevent weak areas in the peptidoglycan layer that lead to cell lysis and death.
The research team led by Martin Thanbichler, Max Planck Fellow at the Max Planck Institute for Terrestrial Microbiology and Professor of Microbiology at the University of Marburg, set out to decipher the composition and function of the autolytic machinery. Their studies focused on the crescent-shaped bacterium Caulobacter crescentus, which is found in freshwater environments and is widely used as a model organism to study basic cellular processes in bacteria.
According to Thanbichler, studying the function of autolysins is a challenging task. “While we know a lot about the synthetic machinery, autolysins have proven to be a tough nut to crack.” Maria Billini, a postdoctoral researcher in Thanbichler’s team, added, “Bacteria usually have many types of autolysins from different enzyme families with different targets. This means that these proteins are very abundant, and the deletion of individual autolysin genes usually has little effect on cell morphology and growth.”
Analysis of potential autolysin regulators by co-immunoprecipitation screening and in vitro protein-protein interaction assays revealed that a factor called DipM plays an important role in bacterial cell wall remodeling. This key regulator, a soluble periplasmic protein, surprisingly interacts with several types of autolysins as well as a cell division factor, showing a promiscuity previously unknown for this type of regulator.
DipM was able to stimulate the activity of two peptidoglycan-cleaving enzymes with completely different activities and folds, making it the first identified regulator that can control both types of autolysins. Notably, the results also show that DipM uses a single interface to interact with its various targets.
“Destruction of DipM leads to loss of regulation at various points of cell wall modification and division process and ultimately kills the cell,” said doctoral student Adrian Izquierdo Martinez, first author of the study. “Its proper function as a coordinator of autolysin activity is essential for proper maintenance of cell shape and cell division in C. crescentus.”
The comprehensive characterization of DipM revealed a novel interaction network, including a self-reinforcing loop that connects lytic transglycosylases and possibly other autolysins to the core of the cell division apparatus of C. crescentus, and probably also to other bacteria. Thus, DipM coordinates a complex autolysin network whose topology is very different from previously studied autolysin systems.
Martin Thanbichler points out, “The study of such multi-enzyme regulators, whose malfunction affects many processes related to the cell wall at the same time, not only helps us understand how the cell wall responds to changes in the cell or the environment.
Adrian Izquierdo-Martinez et al, DipM regulates multiple autolysins and mediates a regulatory feedback loop that promotes cell constriction in Caulobacter crescentus, Communication in Nature (2023). DOI: 10.1038/s41467-023-39783-w
Provided by the Max Planck Society
Citation: A new Achilles heel in the bacterial cell wall (2023, July 20) retrieved 21 July 2023 from https://phys.org/news/2023-07-achilles-heel-bacterial-cell-wall.html
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