Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors

Abstract

Traditional treatment of infectious diseases is based on compounds that kill or inhibit growth of bacteria. A major concern with this approach is the frequent development of resistance to antibiotics. The discovery of communication systems (quorum sensing systems) regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with growth. Compounds that can override communication signals have been found in the marine environment. Using Pseudomonas aeruginosa PAO1 as an example of an opportunistic human pathogen, we show that a synthetic derivate of natural furanone compounds can act as a potent antagonist of bacterial quorum sensing. We employed GeneChip â microarray technology to identify furanone target genes and to map the quorum sensing regulon. The transcriptome analysis showed that the furanone drug speci®c-ally targeted quorum sensing systems and inhibited virulence factor expression. Application of the drug to P.aeruginosa bio®lms increased bacterial susceptibility to tobramycin and SDS. In a mouse pulmonary infection model, the drug inhibited quorum sensing of the infecting bacteria and promoted their clearance by the mouse immune response.

Inhibition of quorum sensing in Chromobacterium violaceum by Syzygium cumini L. and Pimenta dioica L.

“…Oral treatment with a fresh garlic extract for 14 d significantly lowered renal tissue destruction by anti-QS activity against P. aeruginosa infections in the mouse urinary tract infection model [22] . Similarly, furanone C-30, a synthetic analogue of a natural furanone derived from the red alga, administered subcutaneously for 3 d (0.7 µg/ g body weight) to P. aeruginosa infected mice reduced the pulmonary infection by targeting the QS in P. aeruginosa and promoted their clearance by the mouse immune response [23] .…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Diverse sets of furanone compounds have been generated by chemical synthesis (237,238), yielding inhibitors tested most frequently and rigorously on P. aeruginosa quorum sensing and on the V. fischeri LuxR protein heterologously expressed in E. coli, where compounds C-30 and C-56 (Table 3) were the most effective inhibitors (134,237,(239)(240)(241)(242)(243). More recently, additional synthetic schemes have led to new varieties of furanones, but their inhibitory properties remain relatively untested (244,245).…”

“…Exoprotease, pyoverdin, and chitinase activities were reduced, and biofilms were easily penetrated and disrupted by synthetic furanones (240). In vitro, polymorphonuclear leukocytes added to P. aeruginosa biofilms responded with an oxidative burst only toward bacteria pretreated with C-30 (250).…”

“…In one study, C-56 furanone fed to mice orally over a three-day trial period increased survival rates nearly 4-fold over those for untreated animals when challenged with a lethal dose of P. aeruginosa (243). In separate studies, bacterial loads in lungs were three orders of magnitude lower when C-30 furanone treatment was provided subcutaneously every 8 h over 7 days following bacterial challenge (240). Impressively, even if bacterial infection was allowed to establish for 2 days before treatment, P. aeruginosa lasB expression could be suppressed for up to 6 h following a single administration of C-30 intravenously (240).…”

Antibiofilm activity substances derived from coral symbiotic bacterial extract inhibit biofouling by the model strainPseudomonas aeruginosaPAO1

“…Some antifouling substances have recently been identified in microbes and plants (and even animals); these are peptide compounds, such as quorum‐quenching enzyme and small‐molecule compounds (Huang et al ., 2016; Bzdrenga et al ., 2017). Of particular note, is furanone, a traditional inhibitor that is a potent antagonist of Gram‐negative bacteria (Hentzer et al ., 2003), and a type of long‐chain fatty aldehyde, identified as pentadecanal, which acts against Staphylococcus epidermidis biofilm (Casillo et al ., 2017), as well as the 2‐sufonylpyrimidines which can significantly inhibit Pseudomonas aeruginosa biofilm (Thomann et al ., 2016). …”