The Pseudomonas Quinolone Signal (PQS)

Abstract

1IntroductionSince its discovery and initial characterization some 15 years ago by Pesci et al., [1] one particular class of Pseudomonasa eruginosa intercellulars ignaling molecules,t he 4-alkylquinolones (AQs), and the genes involved in the synthesiso ft hese molecules,h ave appeared with refreshing regularity in many studies involving this organism. Herein, we presentahistorical overview of how alkyl quinolones and their signaling pathways were discovered, what these molecules do,w hat gaps remain in our knowledge,a nd how researchers are manipulating AQ signaling for potential therapeutic benefit. Ther eview is not intended to be exhaustive or detailed-the reader is referred to several other excellent monographs for those purposes; [2][3][4] instead, it is intended to providea"taster" of the field and some insights into unresolved questions.ments (las and rhl) of the P. aeruginosa N-acylhomoserine lactone-dependent QS signaling pathways. Herein, we present the discovery and elucidationo fP QS signaling from ah istorical perspective, and also outlines ome of the outstanding research questionst hat still need to be addressed. Finally,w es how how ab etter understanding of the biochemistry underpinning this pathway is leading to the development of new antimicrobial interventions with clear therapeutic potential.Keywords: antimicrobial agents · biological activity · Pseudomonas quinolone signal · quorum sensing · virulence[a] T. Sams

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“…[202] Aset of synthetic AIP-III analogues were found to be excellent inhibitors of all four AgrC receptors in both fluorescence reporter and hemolysis assays.T he most potent inhibitor,D 4A, exhibited picomolar IC 50 values. [193,[214][215][216] One key discovery was that an antagonist of the PQS and HHQ receptor PqsR, 6-nitro-HHQ,can undergo in vivo conversion to 6-nitro-PQS,w hich turns out to be ap otent PqsR modulator. [204] Besides employing AIP analogues to target AgrC,s ome active small molecules were discovered to interact with other gatekeepers of the Agr system.…”

The plant compound rosmarinic acid induces a broad quorum sensing response in Pseudomonas aeruginosa PAO1

“…The function of the pqsE gene is not known, but it is required for the production of multiple PQS-controlled virulence factors and for virulence. However, PqsE was also found to activate PQS-controlled genes in the absence of PqsR and PQS and it was suggested that its regulatory activity requires RhlR (Farrow et al, 2008;Tashiro et al, 2013;Sams et al, 2016).…”

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“…[210,211] Weitere Mçglichkeiten zur Manipulation dieses Stoffwechselweges ergaben sich durch die Fimbrolid-Naturstoffe,w elche phänotypische Veränderungen in verschiedenen Bakterienstämmen zur Folge hatten. [193,[214][215][216] Eine der Schlüsselentdeckungen war die Tatsache,d ass ein Antagonist des PQS/HHQ-Rezeptors PqsR, genannt 6-Nitro-HHQ,invivo eine Umwandlung zu 6-Nitro-PQs eingehen kann, was,wie sich herausgestellt hat, ein potenter PqsR-Modulator ist. [212,213] Zusätzlich zum Eingriff in diese drei klassischen QS-Pfade haben auch verschiedene Spezies-spezifische QS-Systeme wichtiger pathogener Bakterien die Aufmerksamkeit von Wissenschaftlern auf sich gezogen.…”

“…Ausgiebige SAR-Studien brachten vielfältige synthetische PQS/HHQ-Agonisten oder Antagonisten hervor. [193,[214][215][216] Eine der Schlüsselentdeckungen war die Tatsache,d ass ein Antagonist des PQS/HHQ-Rezeptors PqsR, genannt 6-Nitro-HHQ,invivo eine Umwandlung zu 6-Nitro-PQs eingehen kann, was,wie sich herausgestellt hat, ein potenter PqsR-Modulator ist. Basierend auf diesen Ergebnissen wurde ein Carboxamid-Analogon synthetisiert, welches tatsächlich die Pyocyanin-Produktion inhibierte.D arüber hinaus schützte die Verbindung C. elegans in einem Nematoden-Assay vor einer Infektion mit P. aeruginosa PA 14 (Abbildung 15 d).…”