© Copyright 2012 Chemical Biology Ventures Limited. All Rights Reserved. Registered in England & Wales number 7968150. Registered office: 30 Upper High Street, Thame, Oxfordshire, OX9 3EZ. Address for correspondence: 123 Alexander Close, Abingdon, Oxfordshire, OX14 1XD
GyrB/ParE DNA Supercoiling inhibitors
ATPase inhibition
Contact CBV
DNA supercoiling is one of the best antibacterial targets for novel antibacterial discovery. The  very successful fluoroquinolone class of antibacterials are under threat due to emergence & spread of resistance. They target GyrA & ParC enzymes that interact directly with DNA in an ATP-dependent reaction. The ATPase's are endoded by the GyrB & ParE proteins that are now considered to be exploitable. A number of small compound inhibitors have been identified but none has reached the market.
Example:
Discovery of antibacterial DNA supercoiling GyrB/ParE ATPase inhibitors with class leading preclinical efficacy and pharmacology, poised for candidate nomination with a strong unrelated back-up series
Â
Problem:
Identification of novel & efficacious compound series in a crowded IP space
Â
Solution:
A combination of structure-based design & medicinal chemistry approaches led to the discovery of potent & competitive novel antibacterial compounds based on a number of scaffolds including imidazolopyridines, triazolopyridines and benzothiazoles.
Â
Reference Link:
East SP. Bantry White C, Barker O, Barker S, Bennett J, Brown D, Boyd EA, Brennamn C, Chowdhury C, Collins I, Covers-Reignier E, Dymock BW, Fletcher R, Haydon DJ, Gardiner M, Hatcher S, Ingram P, Lancett P, Mortenson P, Papadopoulos K, Smee C, Thomaides-Brears HB, Tye H, Workman J, Czaplewski LG. (2009) DNA gyrase (GyrB)/Topoisomerase IV (ParE) inhibitors: Synthesis and antibacterial activity. Bioorganic Medicinal Chemistry Letters 19, 894-899. PMID19095445
Compounds selected from published patents eg US 2009/0197877 & East et al
Structure-informed medicinal chemistry & patent-busting approaches have delivered several classes of compound with competitive activity in gold standard preclinical models of infections
