Grant: Operating Grant

The life expectancy of Canadians has almost doubled since the discovery of the first antibiotic (penicillin) in 1928. This increase is the direct result of our ability to control infections with antibiotics. However, these benefits are at risk due to the global spread of antimicrobial resistance that affects all classes of known antibiotics. Therefore, researchers are in a desperate hunt for new lead compounds and new antimicrobial targets. Therapies targeting proteases (proteins that cleave other proteins) have had resound success in the treatment of viral infections, including HIV-1 that causes the acquired immuno deficiency syndrome (AIDS) or parasites such as Trypanosoma cruzi, agent of the Changas disease, that kills 50,000 people in Central and South America every year. In bacterial infections, the use of proteases as antimicrobial targets has been quite limited, mainly because of the fragmented understanding of their complex biology. We study ClpP, a protease that pathogenic bacteria require to exhibit its virulence. ClpP is the target of the new class of antibiotics, acyldepsipeptides (ADEPs). Upon binding, ADEPs unleash the protease activity of ClpP causing the indiscriminate degradation of newly synthesized proteins, which kills the bacterium. We use a multidisciplinary approach ranging from molecular to structural biology to gain a detailed understanding of the mechanism of activation of ClpP by ADEPs. Furthermore, we also investigate the mechanisms by which bacteria control the normal activity of ClpP with the final goal of developing new and more potent drugs against this critical enzyme.