期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 35, 页码 13946-13949出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja207142h
关键词
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资金
- National Institutes of Health [CA041101]
- Skaggs Institute for Chemical Biology
- NIH [CA144333]
- JSPS
The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from D-Ala-D-Ala to D-Ala-D-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Psi[C(=NH)NH]Tpg(4)]vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model D-Ala-D-Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model D-Ala-D-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 mu g/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O -> NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH -> O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.
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