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Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase.

ABSTRACT: Bacterial histidine kinases (HKs) are considered attractive drug targets because of their ability to govern adaptive responses coupled with their ubiquity. There are several classes of HK inhibitors; however, they suffer from drug resistance, poor bioavailability, and a lack of selectivity. The 3D structure of Staphylococcus aureus HK was not isolated in high-resolution coordinates, precluding further disclosure of structure-dependent binding to the specific antibiotics. To elucidate structure-dependent binding, the 3D structure of the catalytic domain WalK of S. aureus HK was constructed using homology modeling to investigate the WalK-ligand binding mechanisms through molecular docking studies and molecular dynamics simulations. The binding free energies of the waldiomycin and its methyl ester analog were calculated using molecular mechanics/generalized born surface area scoring. The key residues for protein-ligand binding were postulated. The structural divergence responsible for the 7.4-fold higher potency of waldiomycin than that of its ester analog was clearly observed. The optimized 3D macromolecule-ligand binding modes shed light on the S. aureus HK/WalK-ligand interactions that afford a means to assess binding affinity to design new HK/WalK inhibitors.

SUBMITTER: Radwan A

PROVIDER: S-EPMC7274439 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase.

Radwan Awwad A Mahrous Gamal M GM

PloS one 20200605 6

Bacterial histidine kinases (HKs) are considered attractive drug targets because of their ability to govern adaptive responses coupled with their ubiquity. There are several classes of HK inhibitors; however, they suffer from drug resistance, poor bioavailability, and a lack of selectivity. The 3D structure of Staphylococcus aureus HK was not isolated in high-resolution coordinates, precluding further disclosure of structure-dependent binding to the specific antibiotics. To elucidate structure-d ...[more]

PMID: 32502195

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Project description:Staphylococcus aureus utilizes the two-component regulatory system VraSR to receive and relay environmental stress signals, and it is implicated in the development of bacterial resistance to several antibiotics through the upregulation of cell wall synthesis. VraS inhibition was shown to extend or restore the efficacy of several clinically used antibiotics. In this work, we study the enzymatic activity of the VraS intracellular domain (GST-VraS) to determine the kinetic parameters of the ATPase reaction and characterize the inhibition of NH125 under in vitro and microbiological settings. The rate of the autophosphorylation reaction was determined at different GST-VraS concentrations (0.95 to 9.49 μM) and temperatures (22 to 40°C) as well as in the presence of different divalent cations. The activity and inhibition by NH125, which is a known kinase inhibitor, were assessed in the presence and absence of the binding partner, VraR. The effects of inhibition on the bacterial growth kinetics and gene expression levels were determined. The GST-VraS rate of autophosphorylation increases with temperature and with the addition of VraR, with magnesium being the preferred divalent cation for the metal-ATP substrate complex. The mechanism of inhibition of NH125 was noncompetitive in nature and was attenuated in the presence of VraR. The addition of NH125 in the presence of sublethal doses of the cell wall-targeting antibiotics carbenicillin and vancomycin led to the complete abrogation of Staphylococcus aureus Newman strain growth and significantly decreased the gene expression levels of pbpB, blaZ, and vraSR in the presence of the antibiotics. IMPORTANCE This work characterizes the activity and inhibition of VraS, which is a key histidine kinase in a bacterial two-component system that is involved in Staphylococcus aureus antibiotic resistance. The results show the effect of temperature, divalent ions, and VraR on the activity and the kinetic parameters of ATP binding. The value of the KM of ATP is vital in designing screening assays to discover potent and effective VraS inhibitors with high translational potential. We report the ability of NH125 to inhibit VraS in vitro in a noncompetitive manner and investigate its effect on gene expression and bacterial growth kinetics in the presence and absence of cell wall-targeting antibiotics. NH125 effectively potentiated the effects of the antibiotics on bacterial growth and altered the expression of the genes that are regulated by VraS and are involved in mounting a resistance to antibiotics.

Dataset Information

Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase.

Publications

Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase.

Similar Datasets

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