Abstract
Pseudomonas aeruginosa is a primary driver of morbidity and mortality in cystic fibrosis (CF) patients. Throughout the course of infection, P. aeruginosa undergoes significant evolution and adaptation to the dynamic environment of the CF respiratory tract, leading to the emergence of diverse phenotypes. Among the variants that arise during this process are mutations in the regulatory gene lasR. While clinical significance of LasR deficiency is well recognized, current evidence does not fully elucidate the metabolic changes associated with the absence of this master regulator. To address this, we conducted untargeted metabolic profiling of cell supernatants (exometabolomes) to compare twenty-four P. aeruginosa strains, collected over 3-8 years from ten CF patients classified either as LasR functional (LasR(+)) or LasR non-functional (LasR(-)). We found a highly significant relationship between the LasR phenotype and the global exometabolic profile of the clinical strains. Furthermore, our analysis identified several metabolites whose production appears to be linked to LasR expression. These findings were validated using a loss of function/gain of function approach. This connection between lasR genetic expression, the chronic adaptation of P.aeruginosa to the CF lung environment and the generation of traceable metabolic markers highlights a potential avenue for diagnosing and monitoring respiratory infections caused by this pathogen.