Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

Abstract

Biofilm formation is a universal virulence strategy in which bacteria grow in dense microbial communities enmeshed within a polymeric extracellular matrix that protects them from antibiotic exposure and the immune system. Pseudomonas aeruginosa is an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in cystic fibrosis (CF) patients. The extracellular matrix of P. aeruginosa biofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and nonmucoid isolates of P. aeruginosa produce the Pel and Psl EPS, each of which have important roles in antibiotic resistance, biofilm formation, and immune evasion. Given the central importance of the EPS for biofilms, they are attractive targets for novel anti-infective compounds. In this study, we used a high-throughput gene expression screen to identify compounds that repress expression of the pel genes. The pel repressors demonstrated antibiofilm activity against microplate and flow chamber biofilms formed by wild-type and hyperbiofilm-forming strains. To determine the potential role of EPS in virulence, pel/psl mutants were shown to have reduced virulence in feeding behavior and slow killing virulence assays in Caenorhabditis elegans. The antibiofilm molecules also reduced P. aeruginosa PAO1 virulence in the nematode slow killing model. Importantly, the combination of antibiotics and antibiofilm compounds increased killing of P. aeruginosa biofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronic P. aeruginosa infections.

Pseudomonas aeruginosa type IV minor pilins and PilY1 regulate virulence by modulating FimS-AlgR activity

“…aeruginosa virulence towards C . elegans , but a mechanism of action for those compounds has not been described [ 58 ]. Recently, the small RNA SrbA was shown to modulate both biofilm and virulence towards C .…”

Novel Pyoverdine Inhibitors Mitigate Pseudomonas aeruginosa Pathogenesis

“…Small-molecule inhibitors that target these systems mitigate bacterial pathogenicity, facilitating bacterial clearance by the host. Based on this idea, a number of antivirulence compounds have been proposed for P. aeruginosa , mostly targeting the pathogen’s quorum-sensing systems and biofilm-forming capacity (Vandeputte et al, 2011; Tan et al, 2013; Imperi et al, 2014; Kang and Kirienko, 2017; Paczkowski et al, 2017; van Tilburg Bernardes et al, 2017; D’Angelo et al, 2018).…”

Marine Bacteria, A Source for Alginolytic Enzyme to Disrupt Pseudomonas aeruginosa Biofilms

“…Additionally, high levels of antibiotic resistant pathogens usually ensue, hence the development of non-conventional treatment strategies is urgently needed [16,36]. Many attempts to eradicate biofilms have been efficiently used, including biofilm prevention, disruption, or eradication [8,16,19,37,38]. This work demonstrated that the combined effect of AlyP1400 with conventional antibiotics significantly reduced the notorious P. aeruginosa biofilm.…”

“…Bacterial biofilms represent the dominant bacterial growth lifestyle in different habitats, including natural and clinical environments [1,2,3,4,5]. Bacterial cells switch between the free-living planktonic mode and biofilm growth mode through multiple stages that include adhesion to a substratum, increasing their aggregation into micro-colonies and maturation of biofilms via matrix formation through secretion of extracellular polymeric substances [6,7,8]. It is estimated that 65%–80% of human infections involve biofilms, causing a huge burden on healthcare systems globally [5,9,10].…”