Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in

• -position [14][15]. As a measure of modulation of QS in P. aeruginosa, it was desired to measure the amount of pyocyanin produced by bacterial cultures after treatment with the compounds. This virulence factor is known to be under the regulation of PQS signalling system, and is capable of disrupting many

• important biochemical processes [16]. This leads to numerous deleterious effects on human cells, including inhibited respiration and ciliary action [17]. These effects allow pyocyanin to play a critical role in infection; indeed, mutant P. aeruginosa strains which are unable to produce pyocyanin have been

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• response. In terms of pathogenicity traits, they are involved in the regulation of genes encoding for enzymes responsible for phenazine biosynthesis (pyocyanin production), hydrogen cyanide synthesis, Lectins LecA and LecB and additional genes involved in biofilm formation, enzymes for rhamnolipid

• by pqs QS, pyocyanin is one of the most prominent. This redox-active pigment is responsible for the greenish-blueish colour of P. aeruginosa cultures. It seems that generation of reactive oxygen species is a major mechanism of pyocyanin cytotoxicity [41]. This tricyclic compound is known to induce

• apoptosis in neutrophils, but also to enhance neutrophil extracellular trap formation [42][43]. Both mechanisms impair neutrophil-mediated host defenses. Additionally, it has been hypothesised that pyocyanin functions as an extracellular electron shuttle, contributing to redox homeostasis of P. aeruginosa

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• ) are the two best studied AQs (Figure 1A) [7]. A variety of virulence factors are under control of the pqs quorum sensing system, including the production of elastase, pyocyanin, PA-IL lectin, and rhamnolipids, as well as populations dynamic behaviours such as biofilm formation. However, the exact

• inhibited with 11 even in situ we could not confirm any significantly large inhibition of rhamnolipid or pyocyanin production. Nevertheless, our new compounds may be useful scaffolds for the future development of a novel generation of PqsD inhibitors. Conclusion Electrophilic probes represent powerful tools

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• , UK Bioinformatics Institute, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671 10.3762/bjoc.12.137 Abstract Pyocyanin is a small molecule produced by Pseudomonas aeruginosa that plays a crucial role in the pathogenesis of infections by this notorious opportunistic pathogen. The inhibition

• of pyocyanin production has been identified as an attractive antivirulence strategy for the treatment of P. aeruginosa infections. Herein, we report the discovery of an inhibitor of pyocyanin production in cultures of wild-type P. aeruginosa which is based around a 4-alkylquinolin-2(1H)-one scaffold

• . To the best of our knowledge, this is the first reported example of pyocyanin inhibition by a compound based around this molecular framework. The compound may therefore be representative of a new structural sub-class of pyocyanin inhibitors, which could potentially be exploited in in a therapeutic