Dataset Information

Molecular modelling and docking analysis of pleurocidin (an antimicrobial peptide) like peptides with enterotoxin H from Klebsilla pneumonia.

ABSTRACT: Enterotoxin H is a key molecular target for replication and establishment of Klebsilla pneumonia in the host. Therefore, it is of interest to study the interaction of enterotoxin H with pleurocidin like peptides using molecular modelling (template PDB ID: 1YCE), Lig-Plot (ligand construction) and docking tools for therapeutic consideration. The hydrophobic pocket and the active site residues (Val 13, Met 16, Gly 25, Ala 25, and Ile 28) were identified using Cast P, Molegro and Sitehound tools. Docking results show that the pleurocidin like peptides interacts with the active sites of enterotoxin H with 300.96 docking score with optimal binding features.

SUBMITTER: Bupesh G

PROVIDER: S-EPMC6936665 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Molecular modelling and docking analysis of pleurocidin (an antimicrobial peptide) like peptides with enterotoxin H from Klebsilla pneumonia.

Bupesh Giridharan G Nandini Manickam Sivaraman MS Vasanth Sakthivel S Vijayakumar Tharumasivam Siva TS Amutha Chinnaiah C Prabhu Kaliyaperumal K Balachnadar Vellingiri V

Bioinformation 20191217 11

Enterotoxin H is a key molecular target for replication and establishment of Klebsilla pneumonia in the host. Therefore, it is of interest to study the interaction of enterotoxin H with pleurocidin like peptides using molecular modelling (template PDB ID: 1YCE), Lig-Plot (ligand construction) and docking tools for therapeutic consideration. The hydrophobic pocket and the active site residues (Val 13, Met 16, Gly 25, Ala 25, and Ile 28) were identified using Cast P, Molegro and Sitehound tools. D ...[more]

PMID: 31902985

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Project description:Antimicrobial peptides (AMPs) act either through membrane lysis or by attacking intracellular targets. Intracellular targeting AMPs are a resource for antimicrobial agent development. Several AMPs have been identified as intracellular targeting peptides; however, the intracellular targets of many of these peptides remain unknown. In the present study, we used an Escherichia coli proteome microarray to systematically identify the protein targets of three intracellular targeting AMPs: bactenecin 7 (Bac7), a hybrid of pleurocidin and dermaseptin (P-Der), and proline-arginine-rich peptide (PR-39). In addition, we also included the data of lactoferricin B (LfcinB) from our previous study for a more comprehensive analysis. We analyzed the unique protein hits of each AMP in the Kyoto Encyclopedia of Genes and Genomes. The results indicated that Bac7 targets purine metabolism and histidine kinase, LfcinB attacks the transcription-related activities and several cellular carbohydrate biosynthetic processes, P-Der affects several catabolic processes of small molecules, and PR-39 preferentially recognizes proteins involved in RNA- and folate-metabolism-related cellular processes. Moreover, both Bac7 and LfcinB target purine metabolism, whereas LfcinB and PR-39 target lipopolysaccharide biosynthesis. This suggested that LfcinB and Bac7 as well as LfcinB and PR-39 have a synergistic effect on antimicrobial activity, which was validated through antimicrobial assays. Furthermore, common hits of all four AMPs indicated that all of them target arginine decarboxylase, which is a crucial enzyme for Escherichia coli survival in extremely acidic environments. Thus, these AMPs may display greater inhibition to bacterial growth in extremely acidic environments. We have also confirmed this finding in bacterial growth inhibition assays. In conclusion, this comprehensive identification and systematic analysis of intracellular targeting AMPs reveals crucial insights into the intracellular mechanisms of the action of AMPs.

Project description:IntroductionCationic antimicrobial peptides (CAPs) defend against microbial pathogens; however, certain CAPs also exhibit anticancer activity. The purpose of this investigation was to determine the effect of the pleurocidin-family CAPs, NRC-03 and NRC-07, on breast cancer cells.MethodsMTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) and acid phosphatase cell-viability assays were used to assess NRC-03- and NRC-07-mediated killing of breast carcinoma cells. Erythrocyte lysis was determined with hemolysis assay. NRC-03 and NRC-07 binding to breast cancer cells and normal fibroblasts was assessed with fluorescence microscopy by using biotinylated-NRC-03 and -NRC-07. Lactate dehydrogenase-release assays and scanning electron microscopy were used to evaluate the effect of NRC-03 and NRC-07 on the cell membrane. Flow-cytometric analysis of 3,3'-dihexyloxacarbocyanine iodide- and dihydroethidium-stained breast cancer cells was used to evaluate the effects of NRC-03 and NRC-07 on mitochondrial membrane integrity and reactive oxygen species (ROS) production, respectively. Tumoricidal activity of NRC-03 and NRC-07 was evaluated in NOD SCID mice bearing breast cancer xenografts.ResultsNRC-03 and NRC-07 killed breast cancer cells, including drug-resistant variants, and human mammary epithelial cells but showed little or no lysis of human dermal fibroblasts, umbilical vein endothelial cells, or erythrocytes. Sublethal doses of NRC-03 and, to a lesser extent, NRC-07 significantly reduced the median effective concentration (EC50) of cisplatin for breast cancer cells. NRC-03 and NRC-07 bound to breast cancer cells but not fibroblasts, suggesting that killing required peptide binding to target cells. NRC-03- and NRC-07-mediated killing of breast cancer cells correlated with expression of several different anionic cell-surface molecules, suggesting that NRC-03 and NRC-07 bind to a variety of negatively-charged cell-surface molecules. NRC-03 and NRC-07 also caused significant and irreversible cell-membrane damage in breast cancer cells but not in fibroblasts. NRC-03- and NRC-07-mediated cell death involved, but did not require, mitochondrial membrane damage and ROS production. Importantly, intratumoral administration of NRC-03 and NRC-07 killed breast cancer cells grown as xenografts in NOD SCID mice.ConclusionsThese findings warrant the development of stable and targeted forms of NRC-03 and/or NRC-07 that might be used alone or in combination with conventional chemotherapeutic drugs for the treatment of breast cancer.

Dataset Information

Molecular modelling and docking analysis of pleurocidin (an antimicrobial peptide) like peptides with enterotoxin H from Klebsilla pneumonia.

Publications

Molecular modelling and docking analysis of pleurocidin (an antimicrobial peptide) like peptides with enterotoxin H from Klebsilla pneumonia.

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