The Molecular Architecture of Pseudomonas aeruginosa Quorum-Sensing Inhibitors

Abstract

The survival selection pressure caused by antibiotic-mediated bactericidal and bacteriostatic activity is one of the important inducements for bacteria to develop drug resistance. Bacteria gain drug resistance through spontaneous mutation so as to achieve the goals of survival and reproduction. Quorum sensing (QS) is an intercellular communication system based on cell density that can regulate bacterial virulence and biofilm formation. The secretion of more than 30 virulence factors of P. aeruginosa is controlled by QS, and the formation and diffusion of biofilm is an important mechanism causing the multidrug resistance of P. aeruginosa, which is also closely related to the QS system. There are three main QS systems in P. aeruginosa: las system, rhl system, and pqs system. Quorum-sensing inhibitors (QSIs) can reduce the toxicity of bacteria without affecting the growth and enhance the sensitivity of bacterial biofilms to antibiotic treatment. These characteristics make QSIs a popular topic for research and development in the field of anti-infection. This paper reviews the research progress of the P. aeruginosa quorum-sensing system and QSIs, targeting three QS systems, which will provide help for the future research and development of novel quorum-sensing inhibitors.

Keywords: Pseudomonas aeruginosa; inhibitor; quorum sensing; virulence.

Figure 1

Three main QS systems in P. aeruginosa, las system, rhl system, and pqs system and their signal molecules. Las is indicated in green, rhl is indicated in orange, and pqs is indicated in blue. Las is at the top of the QS hierarchy and influences rhl and pqs. On the other hand, rhl is under the control of both las and pqs.

Figure 2

Las pathways with the QS controls of virulence and other phenotypes. Taking quercetin, naringenin, 4-methylenebut-2-en-4-olideas as examples, they have effects on LasR and lasB.

Figure 3

QS inhibitors from plants acting on las, including vinyl dithiins, isothiocyanates, phenolic compounds, and flavonoids. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) sulfur compounds; (b) key phenolic compounds of ginger; (c) flavonoids.

Figure 4

QS inhibitors from natural products acting on las.

Figure 5

Synthetic compounds based on AHLs serve as QS inhibitors acting on las. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) structure of compounds similar to HSLs; (b) compounds containing a six membered ring; (c) indole based AHL analogues and salicylic acid analogues.

Figure 6

Inhibitors from synthetic compounds acting on las. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) compounds through reductive amination of mucochloric acid and mucobromic acid, compounds contain 2-nitrophenyl fragment; (b) computer-aided approaches designed compounds and compounds containing benzothiazole moiety; (c) unsymmetrical azines, Celecoxib derivatives, dihydropyrrolone analogues, Mannich bases and chrysin derivative; (d) compounds assessed employing a novel specialized multilevel in silico approach.

Figure 7

Rhl pathways with the QS controls of virulence and other phenotypes. Taking RA and 25a as examples, they have effects on RhlR and rhlR, respectively.

Figure 8

QS inhibitors acting on rhl. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) compounds from natural products; (b) AHL analogs; (c) synthetic compounds.

Figure 9

Pqs pathways with the QS controls of virulence and other phenotypes. Taking wogonin and farnesol as examples, they have effects on PqsR, pqsH, and pqsABCDE.

Figure 10

QS inhibitors from natural products acting on pqs.

Figure 11

QS inhibitors from synthetic compounds acting on pqs. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) quinazolinones and chromones-based compounds; (b) compounds containing amide bonds or ureido motifs; (c) compounds containing a six membered ring; (d) compounds containing aminoquinolines and benzamide–benzimidazole series compounds. (e) miscellaneous.

Figure 12

FDA-approved drugs that act as QS inhibitors.

Figure 13

QS inhibitors acting on las and rhl. (a) human sex hormones and their structural relatives; (b) flavonoids; (c) alkaloids, triterpenoids, and phenolic compounds; (d) phytoconstituents from Cassia fistula.

Figure 14

QS inhibitors acting on las and rhl. Groups highlighted in blue are important moieties related to QS inhibitory activity. (a) compounds containing a benzene ring; (b) compounds containing a five membered ring; (c) reported drugs.

Figure 15

QS inhibitors acting on las and pqs or on rhl and pqs. Groups highlighted in blue are important related to showing QS inhibitory activity. (a) cajaninstilbene acid analogues and caffeic acid derivative (b) other compounds acting on las and pqs; (c) compounds acting on rhl and pqs.

Figure 16

QS inhibitors acting on three systems. (a) compounds from natural sources; (b) sulfur-containing compounds; (c) miscellaneous.

Figure 17

QS inhibitors from natural sources with undetermined working mechanisms. (a) flavone; (b) phenolic compounds and alcohols; (c) unsaturated polyenoids; (d) pyranoanthocyanins.

Figure 18

QS inhibitors through artificial synthesis with undetermined working mechanisms. (a) compounds with a benzene ring and indole derivatives; (b) benzimidazole derivatives; (c) glyoxamide derivatives; (d) miscellaneous; (e) Reported drugs.

Figure 19

QS inhibitors from marine sources. (a) compounds from marine sponges; (b) compounds from marine sponge and seagrass; (c) compounds from marine microorganisms.