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The Achilles’ heel of pathogenic bacteria: Their cell wall formation mechanism

Antibiotic resistance phenomena are becoming more and more widespread. Using bio-physical techniques, IRIG researchers have characterized the self-assembled forms of the MreC protein, essential for bacterial wall elongation. Their data could be useful for the development of completely novel inhibitors that could prove to be candidates for future antibiotics.

Published on 26 August 2021
The cell wall plays an essential role in bacterial survival. For decades, the biosynthetic mechanism of its central component, the peptidoglycan, has been exploited as the target for beta-lactam antibiotics (penicillins and cephalosporins). The peptidoglycan forms a three-dimensional structure, comparable to a "fisherman's net" that surrounds most bacteria. It is not only essential for cell stability, but also for the proper execution of the different stages of the cell cycle, such as division and elongation of the wall. Many proteins that participate in the peptidoglycan biosynthesis machinery are essential for bacterial survival. Despite the widespread of resistance to antibiotics in clinics and hospitals worldwide, the bacterial cell wall biosynthesis process remains a target of choice for the possible development of new antibacterial agents.

One of the proteins that plays a central role in the formation of the bacterial wall is MreC, which is believed to form a platform for the stabilization of other proteins involved in cell wall elongation. The work conducted by IRIG researchers shows how MreC is able to self-associate and organize itself into different polymers, such as filaments, and even tubes. The scientists studied MreC from three different pathogenic bacteria: Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa. The protein produced by the latter bacterium, a nosocomial pathogen that causes serious infections, was chosen for structural studies. Structures obtained using cryo-electron microscopy images (data collected at the Glacios microscope at the IBS) as well as with X-ray crystallography (atomic resolution data collected at the LNLS synchrotron in Campinas, Brazil), revealed key regions that lead to the formation of tubular forms of MreC. Any disruption of this polymerized form, such as those generated by the introduction of mutations, impacted not only the ability of MreC to produce polymers in vitro, but also the production of MreC itself in the bacterial cell, a phenomenon that the researchers verified by experiments carried out directly in strains of P. aeruginosa.

The interaction surfaces between the different building blocks of MreC polymers could thus represent a target for the development of totally novel inhibitors that could prove to be candidates for future antibiotics.

Overlay of the cryo-EM map of MreC on a phylogenetic tree of MreC variants present in Proteobacteria.
The circular tree indicates the very high conservation of amino acids shown to be essential for the stability of the MreC structure. One of the six antiparallel filaments that make up the MreC tube is shown in blue and green.

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