Grant: Operating Grant

Chronic bacterial infections are difficult to treat and often cannot be cleared by antibiotics. A devastating example of such infection is the Pseudomonas aeruginosa airway infection in patients with the genetic disease cystic fibrosis. Most patients acquire the infection early in life and remain chronically infected for the rest of their lives despite aggressive antibiotic therapies. These chronic infections cause severe respiratory symptoms, decline in lung function and ultimately death from respiratory failure. One important reason why antibiotics fail to eradicate the P. aeruginosa chronic infections is because they are caused by biofilms. Biofilms are a form of growth where bacteria live in structured clusters, embedded in a polymer matrix. Bacteria growing in biofilms are very tolerant to antibiotics and the host's immune system and the mechanisms of this tolerance are still largely unknown. Our preliminary studies showed that a stress response called the stringent response is important to the ability of P. aeruginosa to grow and stay alive in biofilms, and to be tolerant to antibiotics. The stringent response is a mechanism that allows bacteria to adapt to starvation and many stressful conditions. We also found that the stringent response regulate a family of molecules called 4-hydroxy-2-alkylquinolines and these may be involved in the antibiotic tolerance of biofilms. We are studying how the stringent response is involved in the antibiotic tolerance of P. aeruginosa biofilms. Our studies are focused on understanding how the stringent response regulates these quinoline molecules, on defining the exact role of these molecules in biofilm antibiotic tolerance, and examining whether these findings could be useful for development of future therapies against biofilm infections. With the lack of new antibiotics in development and the severe health burden of biofilm infections, new treatment strategies that target biofilms are much needed.