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J Med Chem. 2015 Mar 12;58(5):2367-77. doi: 10.1021/jm501872s. Epub 2015 Feb 24.

Structure diversification of vancomycin through peptide-catalyzed, site-selective lipidation: a catalysis-based approach to combat glycopeptide-resistant pathogens.

Author information

1
Department of Chemistry, Yale University , P.O. Box 208107, New Haven, Connecticut 06520-8107, United States.

Abstract

The emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, we disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. We have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliphatic hydroxyls on vancomycin, generating three new derivatives 9a, 9b, and 9c. Incorporation of lipid chains into the vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for 9a, 9b, and 9c against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. We have also performed a structure-activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.

PMID:
25671771
PMCID:
PMC4364393
DOI:
10.1021/jm501872s
[Indexed for MEDLINE]
Free PMC Article

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