Bacterial infections
The biochemistry of bacteria and humans differ in several aspects and these differences can be exploited in order to combat pathogenic bacteria. The design of antibiotics strongly depends on the availability of three-dimensional structures of the bacterial enzymes which are to be targeted by antibiotics, given that the enzyme activity is closely linked to its structure. With the recrudescence of infections caused by antibiotic-resistant pathogenic bacteria, it is necessary to develop new therapies aimed at new biochemical targets (such as essential metabolic pathways for bacteria or enzymes responsible for the resistance to antibiotics). A treatment targeting the resistance to antibiotics is promising if it can be combined with a classical antibiotic therapy and increase its efficiency. X-ray crystallography will play a major role by assisting chemists and clinicians in the development of a new generation of antibiotics.
• Albert Berghuis’ research team uses protein crystallography to understand bacterial resistance mechanisms. Peter Pawelek’s team follows another approach in the development of new therapies. His work led to the determination of the protein structure responsible for the absorption of iron, a key element in bacterial growth, by E. coli bacteria. The protein FhuA acts as a receptor for iron-carrying molecules (siderophores). This work opens the way to developing new antibiotics which block the absorption of iron or which use the receptor for siderophores to target bacteria.
• Bacterial infections are a chronic problem for CF patients. René Roy’s research group develops synthetic vaccines against B. cepacia, a microorganism responsible for pulmonary infections in CF patients. This lab also designs anti-adhesins against several E. coli and P. aeruginosa strains, as well as peptides that can be used as universal epitopes of T-cells by binding to MHC-II. The work involves the synthesis of ligands and the characterization of ligand-protein structures.
• Bhushan Nagar’s group studies the role of the innate immune system, which includes cells and mechanisms to provide, in a non-specific manner, immediate defence against an infection. X-ray crystallography allows the characterization of the proteins of Toll-like receptors as well as downstream proteins in signaling pathways.
• Finally, Mirek Cygler’s group is part of the Montreal-Kingston Bacterial Structural Genomics Initiative, which aims to determine the structures of protein complexes involved in bacterial pathologies. This project, subsidized by CIHR and using high-throughput structural biology methods, plays a key role in the identification process of novel targets for antibiotic therapies.