Project 465022

Pseudomonas aeruginosa is a prevalent opportunistic human pathogen. Individuals who are immunocompromised or have breaches in normal barriers are especially susceptible to infections. «Quorum sensing» (QS) is an intercellular communication system used by bacteria to regulate virulence factors and modulate their interactions with hosts. P. aeruginosa control the expression of a wide spectrum of virulence/survival factors through QS. Because of its adaptability, persistence and multi-resistance to antibiotics, control of P. aeruginosa is challenging. Not surprisingly, QS inhibition is an enticing target for alternate therapeutic approaches against pathogens exploiting intercellular communication mechanisms to regulate their virulence, as this would represent an ideal anti-pathogenesis approach likely not prone to resistance, in contrast with antibiotics. But several challenges have slowed down the development of such therapies. For instance, we are increasingly finding that many P. aeruginosa isolates use an alternative QS regulatory circuit to activate virulence and survival that is not typically targeted by traditional QS inhibition approaches. To bypass the current stumbling blocks in using conventional methods in QS inhibition for the development of new therapeutics, we need to target another key element of QS that is well conserved and specific to this pathogen. Interestingly, the functional details of another QS system of P. aeruginosa are increasingly understood. Recent information indicates that one particular key regulatory element of this system, named PqsE, is essential for activation of QS and virulence of this pathogen. In this proposal, we aim to validate this key QS system element as an appropriate target for the development of new QS inhibition approaches as alternatives to antibiotics that will be more efficient and, importantly, specific to control P. aeruginosa.