Novel Class of PqsR Inhibitors to Reduce the Biofilm Formation of P. aeruginosa

Abstract

Microbial biofilms are significant contributors to the pathology of chronic infections. Chronic wounds, cystic fibrosis, diabetic ulcers, periodontitis, and endocarditis are relevant examples of chronic biofilm‐associated disorders. Pseudomonas aeruginosa is a gram‐negative bacterium that forms these biofilms in the wounds, causing increased resistance to antibiotics. It does so through the mechanisms associated with reduced permeability, decreased metabolic rate and altered genetic expression. Recent reports have shown that the use of combination therapy, where antibiotics are supplemented by compounds with the ability to disrupt biofilm integrity, increases the efficacy of the treatment and potentially reduces the rate of the resistance development. P. aeruginosa exerts its virulence program through three intertwined quorum sensing systems: LasR, RhlR and PqsR. Attenuation of the PqsR pathway was shown to affect the release of virulence factors, resulting in inhibited biofilm formation, and increasing the efficacy of antibiotics. In our research, we initiated a study that targeted identification of the structurally different compounds other than acyl homoserine lactone (AHL) moiety with antagonistic properties against PqsR. Using ligand‐based and structure‐based approaches, we performed virtual screening of various databases (ZINC, nine million drug‐like molecules) to identify new pharmacophore scaffolds with potential activity at PqsR. The top scored compounds were synthesized and evaluated against P. aeruginosa PAO1 as an inhibitor of biofilm formation. As a result, we have identified a novel series of PqsR inhibitors capable of reducing biofilm formation by 65% in a concentration range of 1 to 10 μM (in‐vitro static biofilm assay). At the same time, these compounds were shown not to interfere with the bacterial growth at the concentrations up to 200 μM. Altogether, our study identified a novel class of PqsR inhibitor with the ability to reduce the biofilm formation (in‐vitro) and to potentiate the efficacy of traditional antibiotics against P. aeruginosa associated infections.Support or Funding InformationTexas Tech University Health Sciences Center start‐up fund of Dr. Nadezhda GermanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.