N-Terminus alkylation of vancomycin: ligand binding affinity antimicrobial activity and site specific nature of quaternary trimethylammonium salt modification

摘要

A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provide important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogs through an added mechanism of action. The N-terminus modifications disclosed herein were well tolerated, minimally altering model ligand binding affinities (ᴅ-Ala-ᴅ-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification. The results indicate that our earlier observations with the C-terminus modification are sensitive to the site as well as structure of the trimethylammonium salt modification, and are not simply the result of non-specific effects derived from introduction of a cationic charge.