TARGETS

Pseudomonas aeruginosa (PA) is a major human opportunistic pathogen. It causes infections in immune-compromised patients, cystic fibrosis patients and is responsible for many nosocomial infections worldwide. PA provokes acute and chronic infections. The choice between these two modes of infection depends on the ability of PA to switch from a planktonic (free-swimming) to a sedentary (living in a community called a biofilm) lifestyle. In PA, the transition between these two lifestyles is finely regulated by complex regulatory networks involving several two-component regulatory systems. This proposal focuses on the GacS signal transduction network that controls biofilm formation and virulence gene expression. In this network, two trans-membrane sensor kinases, GacS and RetS, interact extensively and function antagonistically via a series of biochemical mechanisms involving multi-modular interactions on both sides of the membrane. This project aims to perform functional and molecular characterization of this regulatory system and identify small molecules to interfere with this network. Our goals will be pursued using interdisciplinary approaches, including genetics, microbiology, biochemistry, structural biology and cellular microscopy. Unravelling the molecular determinants responsible for the GacS-RetS signalling pathway, and identify inhibitors molecules, will contribute to the development of new antibacterial molecules to control PA pathogenicity.