期刊
ACS INFECTIOUS DISEASES
卷 4, 期 10, 页码 1468-1474出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.8b00152
关键词
vancomycin; glycopeptide antibiotics; site-specific mechanism of action; membrane permeabilization; vancomycin peripheral modification
资金
- National Institutes of Health [CA041101]
- NIH [F32 GM114948]
- NATIONAL CANCER INSTITUTE [R01CA041101] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM114948] Funding Source: NIH RePORTER
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.
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