New protein target identified for the development of novel antibiotics

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Brazilian and French scientists were part of an international collaboration, supported by the São Paulo Research Foundation – FAPESP, to elucidate the structure of the elongasome complex and identify new drug targets effective against bacteria of the bacillus genus.

“Our findings pave the way for the development of antibiotics that have a completely different action mechanism to that of the drugs used today,” explained Andréa Dessen, coordinator of the project, which was conducted at the Institute of Structural Biology (IBS) (Grenoble, France) and the National Bioscience Laboratory (LNBio) (São Paulo, Brazil).

“The cell wall is a mesh like a fishing net, made up largely of peptidoglycan, a polymerized blend of sugars and amino acids associated with peptides,” Dessen described. “It protects the bacterium against differences in osmotic pressure and ensures the cell is the right shape. It also contains various factors of virulence.”

Bacterial cell wall biosynthesis is an essential process that requires the PBP2–MreC core complex named the ‘elongasome’. MreC provides structural support and acts as a platform to recruit peptidoglycan biosynthesis enzymes such as Penicillin-Binding Protein 2 (PBP2).

Details of this important interface have previously remained elusive due to the short-lived nature of their interaction. The research team utilized X-ray diffraction crystallography to expound the three-dimensional structure. “In this way, it was possible to understand how the two molecules interact and plan ways of inhibiting this interaction,” Dessen stated.

Next, the team took steps to interfere with this interaction, creating mutant strains of Helicobacter pylori with help from researchers at the Pasteur Institute (France). The strains possessed a mutated MreC protein that could no longer bind to PBP2, and were observed to quickly die when placed in culture due to their inability to acquire the capsule shape.

“The alteration made to MreC really did affect cell wall shape,” clarified Dessen. “So, the experiment proved the importance of the PBP2–MreC complex to elongation of the wall and survival of bacilli. This knowledge can be used to seek molecules capable of interrupting the interaction between these proteins and thereby kill the bacillus.”

This study provides the groundwork for the development of novel antibiotics that could be effective against any bacterial species with elongated cell walls. This group includes Acinetobacter baumannii, a bacterium that the WHO described as one of the most dangerous pathogens of today, alongside the species Klebsiella pneumoniae.

“A woman recently hospitalized in the US died from infection by a strain of K. pneumoniae that’s resistant to 26 different antibiotics. The problem of drug-resistant bacteria is serious and hasn’t been given proper attention by either governments or the pharmaceutical industry. We can no longer ignore it,” Dessen concluded.

Sources: Contreras-Martel C, Martins A, Ecobichon C et al. Molecular architecture of the PBP2–MreC core bacterial cell wall synthesis complex. Nat. Comms. doi:10.1038/s41467-017-00783-2 (2017); http://agencia.fapesp.br/new_target_for_development_of_innovative_antibiotics_is_revealed/26487/

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