N‑Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification

• Published in: ACS infectious diseases 2018-10, Vol.4 (10), p.1468-1474
• Main Authors: Wu, Zhi-Chen, Isley, Nicholas A., Boger, Dale L.
• Format: Article
• Language: English
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.8b00152

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 provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-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 nonspecific effects derived from introduction of a cationic charge.