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1. (WO2018081797) PERIPHERAL MODIFICATIONS ON POCKET-REDESIGNED VANCOMYCIN ANALOGS SYNERGISTICALLY IMPROVE ANTIMICROBIAL POTENCY AND DURABILITY

Pub. No.:    WO/2018/081797    International Application No.:    PCT/US2017/059289
Publication Date: Fri May 04 01:59:59 CEST 2018 International Filing Date: Wed Nov 01 00:59:59 CET 2017
IPC: C07K 7/54
A61K 38/00
Applicants: THE SCRIPPS RESEARCH INSTITUTE
Inventors: BOGER, Dale, L.
Title: PERIPHERAL MODIFICATIONS ON POCKET-REDESIGNED VANCOMYCIN ANALOGS SYNERGISTICALLY IMPROVE ANTIMICROBIAL POTENCY AND DURABILITY
Abstract:
A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides 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. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C- terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl ) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity 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. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.