No abstract

Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), gentamicin-resistant Enterococcus faecalis (GRE), methicillin-resistant Streptococcus pneumoniae (MRS), and vancomycin-resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N-(6-phenylheptyl)demethylvancomycin (12 a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ~18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half-life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation.

The inside cover picture shows the proposed binding mode of a demethylvancomycin analogue (white) with the peptidoglycan of vancomycin-resistant Enterococcus faecalis (teal), in which the NH-p interaction is predicted to compensate for the diminished binding affinity caused by the breaking of a conserved NH … O hydrogen bond in drug-resistant bacteria. For more details, see the Full Paper by Wen-Jiang Zhou, Xun Sun et al. on p. 976 ff.