Small molecules that modulate quorum sensing and control virulence in Pseudomonas aeruginosa

Abstract

Bacteria use small molecule signals to access their local population densities in a process called quorum sensing (QS). Once a threshold signal concentration is reached, and therefore a certain number of bacteria have assembled, bacteria use QS to change gene expression levels and initiate behaviors that benefit the group. These group processes play central roles in both bacterial virulence and symbiosis and can have significant impacts on human health, agriculture, and the environment. The dependence of QS on small molecule signals has inspired organic chemists to design non-native molecules that can intercept these signals and thereby perturb bacterial group behaviors. The opportunistic pathogen Pseudomonas aeruginosa has been the target of many of these efforts due to its prevalence in human infections. P. aeruginosa uses at least two N-acyl l-homoserine lactone signals and three homologous LuxR-type receptors to initiate a range of pathogenic behaviors at high cell densities, including biofilm formation and the production of an arsenal of virulence factors. This perspective highlights recent chemical efforts to modulate LuxR-type receptor activity in P. aeruginosa and offers insight into the development of receptor-specific ligands as potential antivirulence strategies.

Figure 1

Schematic of QS and its role in the symbiotic relationship between V. fischeri and the Hawaiian bobtail squid (Euprymna scolopes). V. fischeri inhabits the light organ of the squid, and uses QS to bioluminesce at high cell densities. In turn, the squid uses this bioluminescence for camouflage and other processes. The lux-type-box is a short, palindromic sequence of DNA recognized by the [AHL:LuxR]₂ complex.

Figure 2

Simplified schematic of QS signaling in P. aeruginosa. Pointed arrows indicate positive regulation, while flattened arrows indicate negative regulation. Ligand:receptor complexes highlighted in this review are shown as filled circles.

Figure 3

Non-AHL derived modulators of LasR. Blue: Agonists; Black: Antagonists. Contributors: Givskov and Høiby (1), Phillips (2), Greenberg (3, 7, and 8), and Givskov (4–6). Greenberg agonist 3 is shown as the corrected structure as determined by later X-ray studies (see text).

Figure 4

Selected heterocyclic AHL analogs active in LasR. Blue: Agonists. Red: Antagonists. Contributors: Kato (9), Blackwell (10), Iglewski (11), and Suga (12–24).

Figure 5

Selected AHL analogs with non-native acyl tails active in LasR. Blue: Agonists; Red: Antagonists. Contributors: Iglewski (25–27), Passador (28 and 29), Meijler (30), Sufrin (31 and 32), and Blackwell (33–44). Note, derivatives from Meijler are irreversible inhibitors of LasR.

Figure 6

Selected compounds active in RhlR. Left: Antagonists; Right: Agonists. Contributors: Suga (45, 46, 49, and 47), Kato (47), Janda (48), and Spring (51 and 52).

Figure 7

Selected compounds active in QscR. Blue: Agonists; Black: Antagonists. Contributors: Blackwell (53–55 and 57), Wood (56), and Park (58).

Figure 8

Image of the X-ray crystal structure of the LasR N-terminal ligand-binding domain (A), close-up views of OdDHL (B), and stereoviews of the non-native agonist 3 (C) bound in the LasR ligand-binding domain. Images reproduced with permission (see Acknowledgements).

Figure 9

QS-active nifuroxazide (antimicrobial agent), chlorzoxazone (known drug: muscle relaxant), and salicylic acid (natural product) identified through virtual screening.