furanone-c-30 and Pseudomonas-Infections

Antimicrobial resistance is one of the current public health challenges to be solved. The World Health Organization (WHO) has urgently called for the development of strategies to expand the increasingly limited antimicrobial arsenal. The development of anti-virulence therapies is a viable option to counteract bacterial infections with the possibility of reducing the generation of resistance. Here we report on the chemical structures of pyrrolidones DEXT 1-4 (previously identified as furan derivatives) and their anti-virulence activity on

Topics: Animals; Anti-Bacterial Agents; Furans; Humans; Hydrocarbons, Halogenated; Mice; Necrosis; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrrolidinones; Quorum Sensing; Type III Secretion Systems; Virulence Factors

Bacterial quorum-sensing (QS) can cause bacterial biofilm formation, thus induce antibiotic resistance and inflammation in chronic bacterial infections. A series of novel 4-arylamidobenzyl substituted 5-bromomethylene-2(5H)-furanones were designed by introducing of brominated furanones into rosiglitazone skeleton, and their potential application in the treatment of chronic bacterial infection was evaluated with regard to their disruption of quorum sensing and anti-inflammatory activities in vitro as well as in animal infection model. Compound 2e displayed both potent QS inhibitory activity and anti-inflammatory activity. Further mechanism studies revealed that the biological effects of 2e and 2k could be attributed, at least in part, to their interaction with PPARγ, and consequent suppression of the activation of NF-κB and MAPK cascades. Importantly, pretreatment with 2e significantly protects mice from lethal-dose LPS challenge. Thus, these data suggest that the dual effective derivative 2e may serve as a valuable candidate for the treatment of chronic bacterial infection.

Topics: 4-Butyrolactone; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Chronic Disease; Humans; Lipopolysaccharides; Male; Mice; Molecular Docking Simulation; NF-kappa B; Nitric Oxide; PPAR gamma; Pseudomonas aeruginosa; Pseudomonas Infections; Quorum Sensing; RAW 264.7 Cells

Novel pyrone-derived quorum sensing (QS) ligands to inhibit the binding of OdDHL to the LasR of Pseudomonas aeruginosa were designed, synthesized and evaluated. Among the analogs, the most potent compound 8 exhibited strong in vitro inhibitory activities against biofilm formation and down-regulated OdDHL/LasR-associated genes by 35-67%. The binding mode of 8 in silico was highly similar to that of the crystal ligand OdDHL in the active site of LasR.

Topics: 4-Butyrolactone; Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Homoserine; Humans; Molecular Docking Simulation; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrones; Quorum Sensing; Structure-Activity Relationship; Trans-Activators

Pseudomonas aeruginosa colonizes the lungs of cystic fibrosis patients causing severe damage. This bacterium is intrinsically resistant to antibiotics and shows resistance against new antimicrobials and its virulence is controlled by the quorum-sensing response. Thus, attenuating its virulence by quorum quenching instead of inhibiting its growth has been proposed to minimize resistance; however, resistance against the canonical quorum quencher furanone C-30 can be achieved by mutations leading to increased efflux. In the present work, the effect of C-30 in the attenuation of the QS-controlled virulence factors elastase and pyocyanin was investigated in 50 isolates from cystic fibrosis patients. The results demonstrate that there is a high variability in the expression of both elastase and pyocyanin and that there are many naturally resistant C-30 strains. We report that the main mechanism of C-30 resistance in these strains was not due to enhanced efflux but a lack of permeability. Moreover, C-30 strongly inhibited the growth of several of the isolates studied, thus imposing high selective pressure for the generation of resistance.

Topics: Anti-Bacterial Agents; Cystic Fibrosis; Down-Regulation; Drug Resistance, Bacterial; Furans; Gene Expression Regulation, Bacterial; Humans; Mutation; Pancreatic Elastase; Permeability; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Quorum Sensing; Respiratory Tract Infections; Virulence Factors

Quorum quenching decreases Pseudomonas aeruginosa virulence factors and biofilm formation, alleviating infections in animal models. Nevertheless, it is usually performed in laboratory strains such as PAO1 and PA14, and studies involving clinical or environmental isolates are scarce. In this work, the effects of ZnO nanoparticles, a potent quorum and virulence quencher for the PAO1 strain, were tested in six clinical strains from cystic fibrosis patients, a furanone C-30 resistant clinical strain from urine, two PA14 gallium resistant mutants, a PA14 C-30 resistant mutant and four environmental isolates. ZnO nanoparticles effectively decreased elastase, pyocyanin, and biofilm formation for most of the strains; regardless their origin or their resistance against the canonical quorum quencher C-30 or the novel antimicrobial gallium. The data indicate ZnO nanoparticles may have a broad spectrum for the quorum quenching of relevant strains and that may be an alternative to treat Ps. aeruginosa recalcitrant infections.. Virulence inhibition by quorum quenchers in Pseudomonas aeruginosa is usually tested in laboratory strains and studies of their effects in relevant clinical and environmental strains are scarce. This study is significant as the effects of ZnO nanoparticles in QS-dependent virulence factor production were tested in six clinical strains from cystic fibrosis patients, a C-30 resistant clinical strain from urine, two PA14 gallium resistant mutants, a PA14 C-30 resistant mutant, and four environmental isolates. ZnO nanoparticles decreased elastase, pyocyanin, and biofilms for most of the strains; indicating they have broad spectrum and may be an alternative to treat Ps. aeruginosa infections.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Cystic Fibrosis; Drug Resistance, Bacterial; Furans; Gallium; Humans; Metal Nanoparticles; Pancreatic Elastase; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Quorum Sensing; Virulence; Virulence Factors; Zinc Oxide

The quorum-quenching compounds brominated furanone C-30 and 5-fluorouracil inhibit the pathogenicity of the Pseudomonas aeruginosa laboratory strains PA01 and PA14; however, there is no report studying the effectiveness of these compounds for clinical isolates. Therefore, the effect of both quorum quenchers on the production of pyocyanin, elastase and alkaline protease of eight clinical strains from children was evaluated. Although both compounds were in general effective for the attenuation of these factors, three strains resistant to C-30 were found. For 5-fluorouracil, PA01 and some clinical isolates showed resistance for at least one phenotype.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Child; Drug Resistance, Bacterial; Endopeptidases; Fluorouracil; Furans; Humans; Pancreatic Elastase; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Quorum Sensing