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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.

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Chitosan microspheres containing phenobarbitone were successfully prepared by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in light liquid paraffin containing sorbitan mono-oleate as a stabilizing agent. Uniform and spherical microspheres, with a loading efficiency up to 57.2%, could be prepared depending on the preparation conditions. The main parameters affecting the preparation and the performance of the prepared microspheres were the molecular weight and concentration of chitosan as well as the concentration of the used stabilizing agent. The incorporation of citric acid into the microspheres was found to increase the formation of a water-soluble gel when the microspheres come in contact with the dissolution medium increasing the rate of drug release. The particle size was shifted towards smaller diameters with increased concentration of sorbitan mono-oleate, up to 4.0% v/v, by use of a lower concentration of chitosan (1.0% w/v) and chitosan with low molecular weight. Rapid initial drug release (20-30% of the incorporated drug) was exhibited in all the prepared microspheres followed by slow release of the remaining amount of the drug. The release rate of the drug from the microspheres prepared from high molecular weight chitosan was slow in comparison with that prepared from medium and low molecular weight chitosan. High concentrations of sorbitan mono-oleate increased the rate of drug release.

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