Discovery of Antagonists of PqsR, a Key Player in 2-Alkyl-4-quinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa

Lu, Cenbin; Kirsch, Benjamin; Zimmer, Christina; Jong, Johannes C. de; Henn, Claudia; Maurer, Christine K.; Müsken, Mathias; Häußler, Susanne; Steinbach, Anke; Hartmann, Rolf W.

doi:10.1016/j.chembiol.2012.01.015

Cited by 114 publications

(127 citation statements)

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“…The most potent inhibitors identified were compounds 19 and 20 (Table 3), which had trifluoromethyl and nitro functional groups, respectively, and IC 50 s of near 50 nM. Further experiments indicated that both compounds were competitive inhibitors of PQS, and direct binding of an antagonist to PqsR was confirmed by surface plasmon resonance (SPR) biosensor experiments (127). Altering the alkyl chains of the antagonists resulted in decreased activity, confirming the importance of an alkyl chain at least 6 carbons in length for both agonism and antagonism of PqsR.…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 93%

“…Antagonist analogues had no observable antibacterial effect, but compound 19 was able to inhibit pyocyanin production by 74% in P. aeruginosa PA14 (at a concentration of 3 M). Surpris- ingly, however, elastase production and rhamnolipid production were not inhibited even at higher concentrations of the compound, but no explanation for these results was provided (127). In a follow-up report by the same group, rational design strategy and SPR biosensor analysis were used to identify additional PqsR binders (229).…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

“…Unfortunately, although various PQS derivatives exhibited agonist and synergistic agonist activity, no antagonism was detected (228). In 2012, however, Lu et al generated and tested a set of HHQ analogues with various side chains and benzene ring substituents and identified the first reported PqsR antagonists (127). Although none of the alkyl side chain analogues showed antagonist activity, the introduction of strong electronwithdrawing groups, such as nitrile, trifluoromethyl, or nitro, at position 6 of the benzene ring resulted in potent antagonistic activity.…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

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Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

665

556

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SUMMARY Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

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Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 93%

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

See 1 more Smart Citation

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

665

556

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“…However, both HHQ and PQS are coinducers of the virulence-associated LysR-type transcriptional regulator PqsR (41). The structural moieties that underpin the interaction between HHQ/PQS and PqsR remain to be fully characterized, although recent studies have reported diverse classes of PqsR antagonists (53)(54)(55) and implicated the hydrophobic pocket situated within the PqsR protein (56). Therefore, in order to assess whether the lead compounds could elicit a virulence response from P. aeruginosa, phenazine production and pqsA promoter activity (57) were monitored in a pqsA mutant where the capacity to produce native HHQ and PQS had been lost.…”

Section: Fig 3 Microscopic Analysis Reveals Altered Biofilm Structurementioning

confidence: 99%

Exploiting Interkingdom Interactions for Development of Small-Molecule Inhibitors of Candida albicans Biofilm Formation

Reen

Phelan

Gallagher

et al. 2016

Antimicrob Agents Chemother

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A rapid decline in the development of new antimicrobial therapeutics has coincided with the emergence of new and more aggressive multidrug-resistant pathogens. Pathogens are protected from antibiotic activity by their ability to enter an aggregative biofilm state. Therefore, disrupting this process in pathogens is a key strategy for the development of next-generation antimicrobials. Here, we present a suite of compounds, based on the Pseudomonas aeruginosa 2-heptyl-4(1H)-quinolone (HHQ) core quinolone interkingdom signal structure, that exhibit noncytotoxic antibiofilm activity toward the fungal pathogen Candida albicans. In addition to providing new insights into what is a clinically important bacterium-fungus interaction, the capacity to modularize the functionality of the quinolone signals is an important advance in harnessing the therapeutic potential of signaling molecules in general. This provides a platform for the development of potent next-generation small-molecule therapeutics targeting clinically relevant fungal pathogens.

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“…However, novel insights on the 16 structure of PqsE, a product of the pqs operon, could lay the foundations for the computer-aided 17 design of PqsE inhibitors [60]. Antagonists of the PqsR were reported for the first time in 2012 [61], 18 and a peculiar mechanism of functional inversion of a PqsR antagonist has been recently described 19…”

Section: Antibodies 24mentioning

confidence: 99%