Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 26, Pages E5052-E5061Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704125114
Keywords
vancomycin; antibiotics; resistant bacterial infections
Categories
Funding
- NIH Postdoctoral Fellowship [F32 GM114948]
- NIH [CA041101]
Ask authors/readers for more resources
Subsequent to binding pocket modifications designed to provide dual D-Ala-D-Ala/D-Ala-D-Lac binding that directly overcome the molecular basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide additional synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin-resistant Enterococci (VRE). Furthermore, it is shown that this type of C-terminal modification may be combined with a second peripheral (4-chlorobiphenyl) methyl (CBP) addition to the vancomycin disaccharide to provide evenmore potent antimicrobial agents [VRE minimum inhibitory concentration (MIC) = 0.01-0.005 mu g/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala-D-Lac binding. Finally, it is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available