Grant: Project Grant

Pseudomonas aeruginosa can cause devastating chronic infections that are nearly impossible to clear with antibiotics. During chronic infections, bacteria grows slowly or as aggregates called biofilms, and this physiological state leads bacteria to become "indifferent" (also termed tolerant) to the toxic effects of antibiotics. Tolerant bacteria thus cause antibiotic treatments to fail and infections to persist or relapse. Unfortunately, current antibiotics are not effective against tolerant bacteria and our understanding of the mechanisms of tolerance is still very limited. The goal of our project is to understand the mechanism of tolerance and to advance the discovery of new antibacterial therapies effective against tolerant bacteria in order to treat chronic infections. We have recently discovered that a bacterial enzyme (called cyclopropane fatty acid synthase CFAS) that modifies the Pseudomonas membrane lipids, making its envelope less permeable when they are in a slow-growing state, and thus shielding it from antibiotics. Conversely, when CFAS is disrupted, Pseudomonas become highly sensitive to antibiotic killing, leading to more effective antibiotic treatments. This suggests that CFAS could be a promising target to discover new drugs that will enhance the efficacy of existing antibiotics. For this project, we propose 1) to study how CFAS makes the Pseudomonas envelope less permeable and renders bacteria more susceptible to antibiotics; 2) to define the importance of CFAS in chronic infections using lab models of biofilms, mouse infection models and human samples of chronic infections; 3) to assess whether CFAS can be a drug target for the discovery of CFAS inhibitors as new drugs that can enhance the efficacy of antibiotics in the treatment of chronic infections.