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GyrB/ParE DNA Supercoiling inhibitors

ATPase inhibition

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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

 

Problem:

Identification of novel & efficacious compound series in a crowded IP space

 

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.

 

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

DNA-I