Assignment of configuration and biochemical studies of synthetic chromomycin A(3) based ligands, and genotypic effects of vancomycin derivaties on bacterial cells.

摘要

Chromomycin A3 (CRA3) is a glycosylated antitumor antibiotic. The sugars of this molecule are known to be involved in the formation of a 2:1 ligand to metal complex with a divalent magnesium ion. This complex binds to the minor groove of DNA. It was proposed that the minimal requirements for forming this complex involved the core chromophore and the trisaccharide portions.;Studies involving the synthesis of this proposed minimal version, the assignment of absolute configuration and biochemical characterization are described here. The method for the previous assignment of the absolute configuration of the chromophore is shown to be unreliable, and a reassignment is presented. Biochemical studies show that a 2:1 complex is formed with the minimal version, but this complex is different from the one formed with the natural product.;Vancomycin is also a glycosylated antibiotic. Vancomycin acts on the cell wall of bacterial cells by binding to the substrate of peptidoglycan. Vancomycin resistance in bacteria is a problem of great interest. Addition of hydrophobic substituents to the sugars of vancomycin was shown to increase the activity of the drug. Specific derivatives also became active against vancomycin resistant organisms. These derivatives were shown to have a different cellular target than vancomycin, and resulted in faster killing of cells.;DNA microarray experiments were performed to look at the effects of the chlorobiphenyl vancomycin derivative on Escherichia coli cells. Differentially regulated genes are reported. A hypothesis is put forth about the mechanism of cell death.