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

• -CoA) is then transferred to an active-site cysteine of the β-ketoacyl-ACP synthase III (FabH)-type enzyme PqsD [26][27]. Subsequently, another CoA-activated substrate comes into play. In analogy to fatty acid synthesis, malonyl-CoA is reacted with the enzyme-bound thioester to yield 2

• , which was supported by compound accumulation studies [48]. PqsD inhibitors PqsD, the second enzyme in the biosynthetic cascade, has been studied intensely by the Hartmann group. Several design strategies have been pursued leading to diverse structural classes of inhibitors (Figure 6). Unfortunately, for

• none of these compounds an X-ray structure in complex with PqsD has been reported although the apoenzyme as well as a substrate-bound form has been successfully crystallized [49]. Using these coordinates, employing in silico methods allowed proposing plausible binding poses for prototypic analogues of

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• (e.g., 24) function as PqsD transition state analogues, and were shown to inhibit the enzyme and reduce bacterial biofilm formation [75]. Numerous approaches target the signal molecule receptor PqsR, and compounds such as 25, 26 and 27 successfully inhibited virulence factor production, biofilm

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

• coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We

• for the development of customized PqsD inhibitors as well as a chemical toolbox to investigate the activity and active site specificity of the enzyme. Keywords: activity-based probes; PqsD; protein labelling; Pseudomonas aeruginosa; quinolones; Introduction The emergence of multi-drug resistant

• ]. The biosynthesis of AQs has been matter of a long-standing debate that could only recently be resolved. Although HHQ could be produced in vitro by a PqsD catalyzed “head-to-head” decarboxylative Claisen condensation of activated anthranilic acid with β-keto fatty acid derivatives [10][11], isotope