Dataset Information

Potential of MurA Enzyme and GBAP in Fsr Quorum Sensing System as Antibacterial Drugs Target: In vitro and In silico Study of Antibacterial Compounds from Myrmecodia pendans.

ABSTRACT:

Background

Increasing the resistance issue has become the reason for the development of new antibacterial in crucial condition. Many ways are tracked to determine the most effective antibacterial agent. Some proteins that are a key role in bacteria metabolism are targeted, including MurA in cell wall biosynthesis and gelatinase biosynthesis-activating pheromone (GBAP) in Fsr Quorum Sensing (QS) system.

Objective

The objective of this research is the analysis of compounds 1-4 from M. pendans as antibacterial and anti-QS activity trough protein inhibition by in silico study; focus on the structure-activity relationships, to appraise their role as an antibacterial and anti-QS agent in the molecular level.

Methods

Both activities of M. pendans compounds (1-4) were analyzed by in silico, compared to Fosfomycin, Ambuic acid, Quercetin, and Taxifolin as a standard. Chemical structures of M. pendans compounds were converted using an online program molview. The compounds were docked to MurA, GBAP, gelatinase and serine protease using Autodock Vina in Pyrx 0.8 followed PYMOL to visualization and proteis.plus program to analyze of the complex.

Results

All compounds from M. pendans bound on MurA, GBAP, gelatinase and serine protease except compound 2. This biflavonoid did not attach to MurA and serine protease yet is the favorable ligand for GBAP and gelatinase with the binding affinity of -6.9 and -9.4 Kcal/mol respectively. Meanwhile, for MurA and serine protease, compound 4 is the highest of bonding energy with values of -8.7 and -6.4 Kcal/mol before quercetin (MurA, -8.9 Kcal/mol) and taxifolin (serine protease, -6.6 Kcal/mol).

Conclusion

Based on the data, biflavonoid acts better as anti-QS than an inhibitor of MurA enzyme while the others can be acted into both of them either the therapeutic agent of anti-QS or antibacterial agent of MurA inhibitor.

SUBMITTER: Apriyanti E

PROVIDER: S-EPMC8778655 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Potential of MurA Enzyme and GBAP in Fsr Quorum Sensing System as Antibacterial Drugs Target: In vitro and In silico Study of Antibacterial Compounds from Myrmecodia pendans.

Apriyanti Eti E Satari Mieke H MH Kurnia Dikdik D

Combinatorial chemistry & high throughput screening 20210101 1

<h4>Background</h4>Increasing the resistance issue has become the reason for the development of new antibacterial in crucial condition. Many ways are tracked to determine the most effective antibacterial agent. Some proteins that are a key role in bacteria metabolism are targeted, including MurA in cell wall biosynthesis and gelatinase biosynthesis-activating pheromone (GBAP) in Fsr Quorum Sensing (QS) system.<h4>Objective</h4>The objective of this research is the analysis of compounds 1-4 from ...[more]

PMID: 32598250

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Project description:BackgroundThe wide spread of antimicrobial resistance in Enterococcus faecalis is a critical global concern, leading to increasingly limited treatment options. The fsr quorum sensing (QS) plays a critical role in the pathogenicity of E. faecalis, allowing bacteria to coordinate gene expression and regulate many virulence factors. Therefore, fsr QS of E. faecalis represents a potential therapeutic target that provides an effective strategy to treat antibiotic-resistant infections induced by E. faecalis.MethodsIn this study, distribution of different virulence factors including, gelatinase, protease, cell surface hydrophobicity and biofilm formation in sixty clinical isolates of Enterococcus faecalis was investigated. Sixty-six compounds were tested for their activity against fsr QS. The minimal inhibitory concentration of the tested compounds was evaluated using the microbroth dilution method. The effect of sub-inhibitory concentrations of the tested compounds on fsr QS was investigated using the gelatinase assay method. Additionally, the effect of potential QS inhibitor on the virulence factors was estimated. Quantitative real-time PCR was used to investigate the effect of the potential inhibitor on fsr QS related genes (fsrB-fsrC) and (gelE-sprE) and virulence associated genes including, asa1 and epbA.ResultsThe assessment of polidocanol activity against the fsr QS system was demonstrated by studying its effect on gelatinase production in E. faecalis clinical isolates. Sub-lethal concentrations of polidocanol showed a significant reduction in gelatinase and protease production by 54% to 70% and 64% to 85%, respectively. Additionally, it significantly reduced biofilm formation (P < 0.01) and interrupted mature biofilm at concentrations of ½, 1 × and 2 × MIC. Furthermore, polidocanol significantly decreased cell surface hydrophobicity (P < 0.01). Polidocanol at ½ MIC showed a significant reduction in the expression of QS genes including fsrB, fsrC, gelE and sprE by 57% to 97% without affecting bacterial viability. Moreover, it reduced the expression of virulence associated genes (asa1 and epbA) (P < 0.01).ConclusionPolidocanol appears to be a promising option for treating of E. faecalis infections by targeting the fsr QS system and exhibiting anti-biofilm activity.

Project description:The emergence of antibiotic resistant bacterial pathogens is increasing at an unprecedented pace, calling for the development of new therapeutic options. Small molecules interfering with virulence processes rather than growth hold promise as an alternative to conventional antibiotics. Anti-virulence agents are expected to decrease bacterial virulence and to pose reduced selective pressure for the emergence of resistance. In the opportunistic pathogen Pseudomonas aeruginosa the expression of key virulence traits is controlled by quorum sensing (QS), an intercellular communication process that coordinates gene expression at the population level. Hence, QS inhibitors represent promising anti-virulence agents against P. aeruginosa. Virtual screenings allow fast and cost-effective selection of target ligands among vast libraries of molecules, thus accelerating the time and limiting the cost of conventional drug-discovery processes, while the drug-repurposing approach is based on the identification of off-target activity of FDA-approved drugs, likely endowed with low cytotoxicity and favorable pharmacological properties. This study aims at combining the advantages of virtual screening and drug-repurposing approaches to identify new QS inhibitors targeting the pqs QS system of P. aeruginosa. An in silico library of 1,467 FDA-approved drugs has been screened by molecular docking, and 5 hits showing the highest predicted binding affinity for the pqs QS receptor PqsR (also known as MvfR) have been selected. In vitro experiments have been performed by engineering ad hoc biosensor strains, which were used to verify the ability of hit compounds to decrease PqsR activity in P. aeruginosa. Phenotypic analyses confirmed the impact of the most promising hit, the antipsychotic drug pimozide, on the expression of P. aeruginosa PqsR-controlled virulence traits. Overall, this study highlights the potential of virtual screening campaigns of FDA-approved drugs to rapidly select new inhibitors of important bacterial functions.

Dataset Information

Potential of MurA Enzyme and GBAP in Fsr Quorum Sensing System as Antibacterial Drugs Target: In vitro and In silico Study of Antibacterial Compounds from Myrmecodia pendans.

Background

Objective

Methods

Results

Conclusion

Publications

Potential of MurA Enzyme and GBAP in Fsr Quorum Sensing System as Antibacterial Drugs Target: In vitro and In silico Study of Antibacterial Compounds from Myrmecodia pendans.

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