Structure–functionality relationship and pharmacological profiles of Pseudomonas aeruginosa alkylquinolone quorum sensing modulators

Abstract

An important paradigm in anti-infective research is the antivirulence concept. Pathoblockers are compounds which disarm bacteria of their arsenal of virulence factors. PqsR is a transcriptional regulator controlling the production of such factors in Pseudomonas aeruginosa, most prominently pyocyanin. In this work, a series of tool compounds based on the structure of the natural ligand 2-heptyl-4-quinolone (HHQ) were used for probing the structure-functionality relationship. Four different profiles are identified namely agonists, antagonists, inverse agonists and biphasic modulators. Molecular docking studies revealed that each class of the PqsR modulators showed distinctive interactions in the PqsR binding domain. It was found that the substituents in position 3 of the quinolone core act as a switch between the different profiles, according to their ability to donate or accept a hydrogen bond, or form a hydrophobic interaction. Finally, it was shown that only inverse agonists were able to strongly inhibit pyocyanin production.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[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.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[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).…”

Flexible Fragment Growing Boosts Potency of Quorum‐Sensing Inhibitors against Pseudomonas aeruginosa Virulence

“…These compounds were further improved regarding their efficacy in P. aeruginosa . We revealed that most potent QSI of this class act as inverse agonists rather than antagonists on the target receptor . In a similar approach, QSI containing a quinazolinone scaffold was discovered and helped resolving the crystal structure of the ligand binding domain of PqsR .…”

“…[22,23] We revealed that most potent QSI of this class act as inverse agonists rather than antagonists on the target receptor. [24] In a similar approach, QSI containing a quinazolinone scaffold was discovered and helped resolving the crystal structure of the ligand binding domain of PqsR. [25] Furthermore, an HTS campaign led to benzamidebenzimidazole compounds showing efficacy in different mouse models, which emphasizes the in vivo relevance of targeting PqsR in infectious diseases.…”