Computational discovery of putative quorum sensing inhibitors against LasR and RhlR receptor proteins of Pseudomonas aeruginosa

Abstract

Drugs have been discovered in the past mainly either by identification of active components from traditional remedies or by unpredicted discovery. A key motivation for the study of structure based virtual screening is the exploitation of such information to design targeted drugs. In this study, structure based virtual screening was used in search for putative quorum sensing inhibitors (QSI) of Pseudomonas aeruginosa. The virtual screening programme Glide version 5.5 was applied to screen 1,920 natural compounds/drugs against LasR and RhlR receptor proteins of P. aeruginosa. Based on the results of in silico docking analysis, five top ranking compounds namely rosmarinic acid, naringin, chlorogenic acid, morin and mangiferin were subjected to in vitro bioassays against laboratory strain PAO1 and two more antibiotic resistant clinical isolates, P. aeruginosa AS1 (GU447237) and P. aeruginosa AS2 (GU447238). Among the five compounds studied, except mangiferin other four compounds showed significant inhibition in the production of protease, elastase and hemolysin. Further, all the five compounds potentially inhibited the biofilm related behaviours. This interaction study provided promising ligands to inhibit the quorum sensing (QS) mediated virulence factors production in P. aeruginosa.

Curcumin from Curcuma longa affects the virulence of Pectobacterium wasabiae and P. carotovorum subsp. carotovorum via quorum sensing regulation

“…Therefore, it is envisaged that the inhibition of such QS mechanism in soft rotting bacterial pathogens could ultimately reduced their pathogenicity on plant species. Several studies have already reported that plant extracts and plantderived compounds will effectively interfere with AHL mediated QS system, without inhibiting the bacterial growth (Adonizio et al 2006;Annapoorani et al 2012a;Annapoorani et al 2012b;Bakkiyaraj et al 2013;Bodini et al 2009;Brackman et al 2009;Choo et al 2006;Packiavathy et al 2012;Packiavathy et al 2013;Rudrappa and Bais 2008). Hence, our research aims to investigate the QSI potential of curcumin against soft rot causing P. wasabiae SCC3193, P. carotovorum subsp.…”

“…Two different experimental setups were made. In experimental setup 1: curcumin (10 μg/ml) was added at 0 h of incubation in test bacterial pathogens and incubated for 24 h, in experimental setup 2: curcumin (10 μg/ml) was added to the cultures only after 18 h of incubation and extended up to 24 h. After 24 h of incubation, the CFCS from both setups were obtained and subjected to protein degradation assay to analyse the degradation or binding properties of curcumin on the enzymes (Annapoorani et al 2012b). …”

Identification of Five Structurally Unrelated Quorum-Sensing Inhibitors of Pseudomonas aeruginosa from a Natural-Derivative Database

“…In recent years, SB-VS approaches have also been used in the search for novel QSIs, and here are a few recent examples: (i) discovery of hamamelitannin, a natural compound from Hamamelis virginiana that inhibits QS in drug-resistant Staphylococcus aureus and Staphylococcus epidermidis (53); (ii) identification of novel AI-2 QS inhibitors of Vibrio harveyi by SB-VS with the crystal structure of LuxP (54); (iii) discovery of a compound from Melia dubia bark extract which could inhibit the QS regulator SdiA, present in uropathogenic E. coli (UPEC) (55); (iv) discovery of five QSIs from an SB-VS of 1,920 natural compounds against the LasR and RhlR receptor proteins (56); and (v) discovery of 5 inducers and 3 inhibitors of LasR through a SB-VS of 800,000-plus compounds from the Chembridge library through a pharmacophore-based approach for compounds similar to OdDHL (57).…”

Resistance to Quorum-Quenching Compounds

“…Molecular alignment of receptor proteins (e.g., LuxR-type proteins) indicate that there are preserved motifs in the residues of Y53, Y71, W57, D70, and W85 of TraR and Y56, Y64, W60, D73, and W88 of LasR and that the amino acid residues D70, W57, and Y53 in TraR and D73, W60, Y56, and S129 in LasR are important for interacting with the autoinducer analogs (24). The autoinducer analogs rosmarinic acid, naringin, chlorogenic acid, morin, and mangiferin have been studied through in silico docking analysis, and the analyses demonstrated that these compounds can inhibit the production of protease, elastase, and hemolysin (25). In addition, five inducers and three inhibitors which are molecularly distant from the native autoinducer N-3-oxododecanoyl-Lhomoserine lactone have been investigated as potential QQ compounds (26).…”