Theoretical and structural analysis of the active site of the transcriptional regulators LasR and TraR, using molecular docking methodology for identifying potential analogues of acyl homoserine lactones (AHLs) with anti-quorum sensing activity (original) (raw)
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Journal of Molecular Graphics and Modelling, 2007
A comparative molecular modelling study of acyl homoserine lactones-dependent transcriptional regulators (TraR, SdiA, LuxR and LasR) involved in bacterial quorum sensing (QS) revealed a high structural homology of their active site. Docking studies within the active site of TraR of fixed conformations obtained using molecular mechanics calculations showed that TraR, for which the crystalline structure is known, is a relevant model for the study of other protein-ligand interactions in the same protein family. Structure-activity relationships of AHLs derived QS modulators including carboxamides, sulfonamides and ureas were thus investigated. The results show that Tyr61, a residue conserved in the LuxRproteins family, is involved in attractive interactions with aromatic carboxamide antagonists. Tyr53, Tyr61 and Asp70, conserved residues, are implicated in both the development of additional hydrogen bonds and attractive interactions with the N-sulfonyl homoserine lactones and AHLs derived ureas antagonists. #
Naturally Occurring Quorum Sensing Inhibitors for Pseudomonas aeruginosa by Molecular Modeling
The quorum-sensing (QS) system allows organisms to communicate and form virulence factors such as biofilm. Pseudomonas aeruginosa is one of the Gram-negative bacteria leaving many casualties every year. In the past years, the bacteria's QS system has gained attention as a valuable target to design and develop new efficient antibiotics. Nature has always been an inspiration source for designing many new medicines, and using natural compounds is always the first approach to discover and design new drugs. Here, we in-silico studied 24,000 natural compounds, including first and secondary metabolites, on five known QS-related receptors of Pseudomonas aeruginosa. After several levels of screening, compounds NP-1 (3,6′-di-O-sinapoylsucrose), NP-2 (ZINC000257412737), NP-3 (3-O-β-D-rutinosin) showed the best inhibition activity on AHL synthase LasI with the docking scores of-8.988,-8.690, and-8.925 kcal/mol, respectively. Also, NP-101 (ZINC000077264779), NP-102 (ZINC000225518732), and NP-103 (ZINC000096269362) were selected for LasR-LBD with the scores of-13.355,-13.038, and-12.917 kcal/mol, respectively. In the case of LasA, docking scores of-13.357,-10.796, and-10.564 kcal/mol were obtained for NP-201 (Parishin), NP-202 (7-O-galloyl-Dsedoheptulose), and NP-203 (1,2-di-O-galloyl-6-O-p-coumaroyl-β-D-glucose), respectively. Furthermore, when the LasR-TP4 was the target, the best results were observed from NP-301 (ZINC000514288841), NP-302 (ZINC000077264754), and again NP-103 (ZINC000096269362), in which they showed docking scores of-13.175,-13.020, and-12.998 kcal/mol, respectively. Finally, the highest docking scores belonged to NP-401 (ZINC000150351649), NP-402 (ZINC000150351636), NP-403 (ZINC000150349056), which interacted with the ATPase Type IV pilus with the docking scores of-16.274,-15.773, and-15.405 kcal/mol, respectively.
JOURNAL OF SCIENTIFIC RESEARCH
Use of antibiotics for a long time has resulted in the evolution of multiple drug resistance pathogenic bacterial strains, leading to difficulties to treat bacterial infections. Nowadays, the problem of bacterial resistance can be overcome by targeting the virulence mechanism of the bacterial infection process which has been established as the molecular target for the discovery of antibacterial agents. One of the extensively studied gram positive bacterial QS mechanisms is accessory gene regulator (agr) QS mechanism responsible for the secretion of different virulence factors. Expression of genes associated with the virulence factors secretion of agr quorum sensing system can be attenuated by the inhibition of AgrA-DNA binding interactions. In this study we docked four natural compounds (actinomycin D, obacunone, ursolic acid and ansamitocin P-3) with five homology modelled AgrA proteins of five pathogen, Streptococcus pyogenes, Listeria monocytogenes, Enterococcus faecalis, Chlamydia trachomatis and Macrococcus canis and also with their template protein (PDB ID: 4G4K) of Staphylococcus aureus. Normal mode analyses of the docked complexes were performed in order to obtain different parameters like deformability and B-factor related to stability of the complexes. Drug likeness of the compounds was also studied.
ChemBioChem, 2008
Bacterial quorum sensing is mediated by low molecular‐weight signals and plays a critical role in both the pathogenesis of infectious disease and beneficial symbioses. There is significant interest in the development of synthetic ligands that can intercept bacterial quorum sensing signals and modulate these outcomes. Here, we report the design and comparative analysis of the effects of ∼90 synthetic N‐acylated homoserine lactones (AHLs) on quorum sensing in three Gram negative bacterial species and a critical examination of the structural features of these ligands that dictate agonistic and antagonistic activity, and selectivity for different R protein targets. These studies have revealed the most comprehensive set of structure–activity relationships to date that direct AHL‐mediated quorum sensing and a new set of chemical probes with which to study this complex signaling process. Furthermore, this work provides a foundation on which to design next‐generation quorum sensing modulato...
N-Sulfonyl homoserine lactones as antagonists of bacterial quorum sensing
Bioorganic & Medicinal Chemistry Letters, 2004
A series of 11 new analogues of N-acylhomoserine lactones in which the carboxamide bond was replaced by a sulfonamide one, has been synthesised. These compounds were evaluated for their ability to competitively inhibit the action of 3-oxohexanoyl-L L-homoserine lactone, the natural ligand of the quorum sensing transcriptional regulator LuxR, which in turn activates expression of bioluminescence in the model bacterium Vibrio fischeri. Several compounds were found to display antagonist activity. Molecular modeling suggests that the latter prevent a cascade of structural rearrangements necessary for the formation of the active LuxR dimer.
A simple screening protocol for the identification of quorum signal antagonists
Journal of Microbiological Methods, 2004
Quorum sensing (QS) is a mechanism by which diverse microorganisms can control specific processes in response to population density. A relatively well-known form of QS among Proteobacteria involves production and subsequent response to acylated homoserine lactones (AHLs). Quorum sensing inhibition (QSI), targeting AHL-dependent signaling, has been reported as a strategy for the control of biofilm formation used by several marine organisms. We developed a simple soft agar overlay protocol, based on pigmentation inhibition, to rapidly screen for the presence of potential QSI by bacteria and plants. For bacterial screens, test organisms are first streaked onto their appropriate media and incubated overnight. For plant screens, the plant material (leaf, stem, flower, etc.) is placed onto LB agar. The bacterial growth or plant samples are then covered with an overlay of LB soft agar containing an inoculum of either Pseudomonas aureofaciens 30 -84 or Chromobacterium violaceum ATCC 12472 (indicator cultures) and then incubated overnight. These indicator bacteria regulate pigment production by N-hexanoyl-HSL (C6-HSL) QS and are readily inhibited by AHL analogues and other antagonists. QSI is indicated by the lack of pigment production of the indicator culture in the vicinity of the test sample. Growth inhibition of the indicator culture indicates possible antibiotic production. Two different biosensor organisms based on derivatives of Agrobacterium tumefaciens and C. violaceum, capable of detecting a range of AHLs were used to determine whether QSI is due to the production of interfering AHLs competing with the C6-HSL regulation of C. violaceum and P. aureofaciens pigment production. This simple protocol will facilitate the screening of multiple organisms for the production of potential antifouling compounds. D
A series of Acyl homoserine lactone derivatives against quorum sensing (QS) enhanced transcriptional regulator SdiA of S. typhimurium were used to establish the physicochemical and structural requirements for the inhibition of QS using 2D-and 3D-QSAR methods. The QSAR model was developed by employing 35 compounds as a training set and the predictive ability was assessed by a test set of 12 compounds. The best 2D-QSAR model for the prediction of SdiA, quorum sensor inhibitory activity has been developed using Multiple Linear Regression (MLR) method (giving r 2 = 0.8012 and q 2 = 0.657), Principal Component Regression (PCR) method (giving r 2 = 0.8104 and q 2 = 0.625), and Partial Least Squares Regression (PLS) method (giving r 2 = 0.8023 and q 2 = 0.648). The best model for 3D-QSAR has been obtained using Comparative Molecular Field Analysis (CoMFA) method, giving r 2 = 0.896 and q 2 = 0.772. The 2D-QSAR results revealed that the most important descriptors for predicting the anti-quorum sensing activity were alignment-independent descriptors and the topology index descriptors. The 3D-QSAR results of CoMFA contour maps impart some important structural features-like electronegative substituent (Br, Cl, F) on lactone ring favors the strong inhibitory activity. These results will be further useful for development of new quorum sensing inhibitors with structural diversity.
Bioorganic & Medicinal Chemistry Letters, 2002
A series of 22 novel synthetic N-acyl-homoserine lactone analogues has been evaluated for both their inducing activity and their ability to competitively inhibit the action of 3-oxo-hexanoyl-l-homoserine lactone, the natural inducer of bioluminescence in the bacterium Vibrio fischeri. In the newly synthesized analogues, the extremity of the acyl chain was modified by introducing ramified alkyl, cycloalkyl or aryl substituents at the C-4 position. Most of the analogues bearing either acyclic or cyclic alkyl substituents showed inducing activity. In contrast, the phenyl substituted analogues displayed significant antagonist activity. We hypothesized that the antagonist activity of the phenyl compounds may result from the interaction between the aryl group and aromatic amino acids of the LuxR receptor, preventing it from adopting the active dimeric form. #
Quorum sensing (QS) is a cell density-dependent regulation of virulent bacterial gene expression by autoinducers that potentially pertains in the epidemic of bacterial virulence. This study was initially designed to evaluate the effect of 5 phenolic compounds in the modulation of QS and virulence factors of Chromobacterium violaceum and Pseudomonas aeruginosa, and to determine the mechanisms of their effects. Biosensor strains were used to assess antibacterial and anti-QS effect of these compounds. Only methyl gallate (MG) among these compounds demonstrated profound anti-QS effect in the preliminary study, and thus only MG was utilized further to evaluate the effects on the synthesis and activity of acyl homoserine lactone (AHL) in C. violaceum and on the modulation of biofilm, motility, proteolytic, elastase, pyocyanin, and rhamnolipid activity in P. aeruginosa. Finally, the effect of MG on the expression of QS-regulated genes of P. aeruginosa was verified. MG suppressed both the synthesis and activity of AHL in C. violaceum. It also restricted the biofilm formation and other QS-associated virulence factor of P. aeruginosa. MG concentration-dependently suppressed the expression of lasI/R, rhlI/R, and pqsA of P. aeruginosa and was non-toxic in in vitro study. This is the first report of the anti-QS mechanism of MG. Quorum sensing (QS) is an inter-cellular communication system of bacteria that is used to collectively control group behaviors 1, 2. This process depends on the production, release, and group-wide detection of signal molecules which are known as autoinducers. The autoinducers in gram-negative bacteria are typically homoserine lactones (HSLs) 1, 2. LuxI-type enzymes involved in the production of HSLs, and LuxR-type cytoplasmic proteins act as the receptors of HSL 1, 2. LuxR-type receptors can be stabilized by binding with autoinducers, and this stabilization enables the dimerization, binding of DNA, and the transcription of QS target genes 3, 4. LuxI/R signaling cascades are essential for the virulence in many pathogenic bacteria, and the virulence of these bacteria can be prevented by disabling these circuits with small molecules 2. C. violaceumis an aquatic, saprophyte, gram-negative bacterium that occasionally acts as a pathogen of extreme virulence, and causes fatal septicemia, lung and liver abscesses, and skin lesions 5. C. violaceum produces violacein pigment in response to QS regulated gene expression 6. Considering this characteristic, this bacterium is widely used to study the inhibition of acyl homoserine lactone (AHL)-dependent QS by diverse compounds 7–9. The utilization of this bacterium is also very common in the assessment of short chain AHL production, because of the tight AHLs-QS control over the production of violacein pigment 10. Pseudomonas aeruginosa is an oppor-tunistic pathogen that causes morbidity and mortality in immune-compromised patients such as cystic fibrosis, AIDS, cancer patients and severe burn victims 11. This organism depends on two key LuxI/R QS systems, namely