title: 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 aeruginosais an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in cystic fibrosis (CF) patients. The extracellular matrix ofP. aeruginosabiofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and nonmucoid isolates ofP. aeruginosaproduce 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 thepelgenes. Thepelrepressors 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/pslmutants were shown to have reduced virulence in feeding behavior and slow killing virulence assays inCaenorhabditis elegansThe antibiofilm molecules also reducedP. aeruginosaPAO1 virulence in the nematode slow killing model. Importantly, the combination of antibiotics and antibiofilm compounds increased killing ofP. aeruginosabiofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronicP. aeruginosainfections.
authors.affiliation: Faculty of Medicine, Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.|Snyder Institute of Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: van Tilburg Bernardes
authors.affiliation: Faculty of Medicine, Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Charron-Mazenod
authors.affiliation: Faculty of Medicine, Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Reading
authors.affiliation: Faculty of Medicine, Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.|Faculty of Science & Technology, Athabasca University, Athabasca, Alberta, Canada.
authors.forename: Shauna L
authors.initials: SL
authors.lastname: Reckseidler-Zenteno
authors.affiliation: Faculty of Medicine, Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada slewenza@ucalgary.ca.|Snyder Institute of Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.|Faculty of Science & Technology, Athabasca University, Athabasca, Alberta, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Lewenza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D018441:Biofilms / Q000254:growth & development*; D017173:Caenorhabditis elegans / Q000382:microbiology; D004269:DNA, Bacterial / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000382:microbiology; D057166:High-Throughput Screening Assays; D006801:Humans; D011135:Polysaccharides, Bacterial / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity*; D012097:Repressor Proteins / Q000378:metabolism / Q000494:pharmacology*; D014774:Virulence / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D011135:Polysaccharides, Bacterial; D012097:Repressor Proteins
keywords: Caenorhabditis elegans; Pel matrix; Pseudomonas aeruginosa; antibiofilm; antivirulence; exopolysaccharides; high-throughput screening