Small Molecule Biofilm Inhibitors with Antivirulence Properties against Pseudomonas aeruginosa

Abstract

The opportunistic pathogen Pseudomonas aeruginosa grows within biofilms in the Cystic Fibrosis airways, leading to chronic, life-threatening infections. Biofilms are dense communities of bacteria surrounded by a protective polymeric extracellular matrix comprised of exopolysaccharides (EPS), proteins and extracellular DNA. The two major EPS molecules produced by P. aeruginosa are the Pel and Psl. Considering the essential role of EPS in biofilm formation, antimicrobial resistance and immune evasion, we developed a high-throughput gene expression screen for the identification of small molecules that reduce both pel and psl gene expression. Testing of the identified pel/psl repressors demonstrated their antibiofilm activity against static and flow biofilm models. Moreover, these antibiofilm molecules also reduce PAO1 virulence in a nematode infection model, as well as increase P. aeruginosa biofilm susceptibility to antibiotic killing. These small molecules represent a novel anti-infective strategy for the possible adjuvant treatment of chronic P. aeruginosa infections.