Targeting the pqs quorum sensing system for the discovery of novel anti-Pseudomonas aeruginosa pathoblockers
Progetto Bacterial resistance to antibiotics represents a growing threat to global public health. Due to its multidrug resistance, Pseudomonas aeruginosa causes infections associated with high mortality and morbidity, leading to a heavy burden on the healthcare system, economy, and resource utilization. Searching for new targets to develop new antimicrobials and antibacterial strategies has become, therefore, essential for overcoming resistance.
The aim of the present Project is to define a robust knowledge for developing a non-conventional pathoblocker strategy to fight infections caused by P. aeruginosa. Specifically, an antivirulence approach based on the inhibition of pqs Quorum Sensing (QS) system will be explored by identifying novel PqsR inhibitors with the potential for quenching P. aeruginosa virulence and pathogenicity.
The research design plans first to design and synthesize around 60 potential PqsR inhibitors. These inhibitors will undergo to in vitro and in vivo antivirulence assays, structure-activity relationship, and mechanism of action analyses. Next, the most effective candidates (best 8-10) will be evaluated in vitro for their quenching activity against several pqs QS-related virulence phenotypes using a set of P. aeruginosa hypervirulent clinical strains. QS quenching will be then confirmed by measuring QS signaling molecule production and QS gene expression. Combination studies will also be performed to assess the PqsR inhibitor/antibiotic synergistic effect. Based on the findings from in vitro cytotoxic assays and the evaluation of selected drug-like properties, the best (1-2) PqsR inhibitors will finally be exploited for their antivirulence activity in murine models of wound, lung, and bloodstream infections.
The results expected by the completion of this multidisciplinary project will substantially contribute to the identification of PqsR inhibitors effective in quenching the pathogenicity of P. aeruginosa. This will result in a positive impact on human health and quality of life with positive
indirect repercussions also on global expenses related to curing infections by P. aeruginosa.