Controlling chronic Pseudomonas aeruginosa infections by strategically interfering with the sensory function of SagS.

Abstract

The hybrid sensor SagS plays a central role in the formation ofPseudomonas aeruginosabiofilms,by enabling theswitch from the planktonic to the biofilm mode of growth and by facilitating the transition of biofilm cellsto a highly tolerant state. In this study, we examined the importance of the SagS key amino acid residues associated with biofilm formation (L154) and antibiotic tolerance (D105) in P. aeruginosavirulence. Recombinant P. aeruginosa ΔsagS and ΔsagS chromosomally expressing wild-typesagS, or its two variants D105A and L154A, were tested for their potential to form biofilms and cause virulence in plants and mouse models of acute and chronic pneumonia. Although mutation ofsagS did not alter P. aeruginosa virulence during acute infections, a significant difference in pathogenicity ofsagS mutants was observed during chronic infections, with the L154A variant showing reduced bacterial loads in the chronic pneumonia model, while interference with the D105 residue enhanced the susceptibility ofP. aeruginosa biofilms during tobramycin treatment. Our findings suggest that interference with the biofilm or tolerance regulatory circuits of SagS affectsP. aeruginosapathogenicity in chronic but not acute infections, and reveal SagS to be a promising new target to treatP. aeruginosabiofilm infections.