Glyceryl trinitrate is a novel inhibitor of quorum sensing in Pseudomonas aeruginosa

Abstract

Background: Targeting quorum sensing is an alternative approach to antibiotics.Targeting quorum sensing-regulated virulence will disarm the pathogen without exerting pressure on its growth. As a result, emergence of resistance is avoided and the immune system can easily eradicate bacteria.

Objectives: Investigation of the possible inhibition of quorum sensing-regulated virulence of Pseudomonas aeruginosa by glyceryltrinitrate.

Methods: The quorum sensing inhibiting activity of glyceryl trinitrate was assessed by inhibition of violacein production in Chromobacterium violaceum ATCC 12472. Its ability to inhibit pyocyanin, protease, biofilm and tolerance to oxidative stress was evaluated. Docking study was performed to study the interference of glyceryl trinitrate with the binding of autoinducers with LasR and rhlR receptors.

Results: Glyceryl trinitrate exerted a significant biofilm inhibiting and eradicating activities. It decreased the production of quorum-sensing dependent violacein production. It significantly inhibited the production of pyocyanin and protease and diminished the tolerance against oxidative stress. Molecular docking study showed that glyceryl trinitrate interferes with the binding of autoinducers to their receptors. It could bind to Las Rand rhlr receptors with binding energy of -93.47 and -77.23, respectively.

Conclusion: Glyceryl trinitrate can be an antivirulence agent in the treatment of Pseudomonas aeruginosa topical infections such as burn infections.

Keywords: Glyceryl trinitrate; Pseudomonas aeruginosa; quorum sensing; virulence inhibition.

Figure 1

(a) Inhibition of biofilm formation by GTN, (b) eradication of established biofilms by GTN. The error bars indicate the standard deviations of two measurements

Figure 2

Inhibition of protease by GTN. The error bars indicate the standard deviations of three measurements

Figure 3

Inhibition of pyocyanin production by GTN. The error bars indicate the standard deviations of three measurements

Figure 4

Resistance of Pseudomonas aeruginosa PAO1 strain to oxidative stress in absence (a) and presence (b) of GTN. The zone of inhibition of growth of PAO1 by hydrogen peroxide increased in the presence of GTN

Figure 5

The Molecular docking of a) GTN into the active site of LasR enzyme 3D (Top) and 2D schematic view of the binding (Bottom), b) natural ligand (Top) and C30 furanone (Bottom) into the active site of LasR enzyme 3D (Left) and 2D schematic view of the binding (Right)

Figure 6

The Molecular docking of C4-BHL (Top) and GTN (Bottom) into the active site of rhlr receptor model 3D (Left) and 2D schematic view of the binding (Right)