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Product-focused antibacterial re-engineering Turning knowledge into medicine

GyrB/ParE Dual-targeting DNA Supercoiling inhibitors

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Abgentis News

Abgentis continues to explore the potential of the novobiocin-analogue GYR12 in combination with antibiotic potentiators such as colistin, polymixin B or pentamidine.
At pharmacologically achievable exposures GYR12/colisitin has broad-spectrum activity including E. coli, K. pneumoniae, A. baumannii and P. aeruginosa.
We have recently shown that spontaneous resistance frequency development to the combination is low e.g. <10e-9, consistent with suppression of resistance in use.
The combination of GYR12 with a potentiator such as colistin or pentamidine has the potential to bring the GyrB/ParE targets into clinical use to treat drug-resistant Gram-ve bacterial infections.

Abgentis’ goal is to provide a new broad-spectrum IV/oral antibacterial to treat acute and chronic, life-threatening and drug-resistant infections. Based on a previously marketed but uncompetitive compound, Abgentis' “fast-follower” programme will deploy unique insight into the structure-activity relationships, microbiology, pharmacology and efficacy of antibacterial DNA supercoiling inhibitors to rapidly re-engineer and optimise, to create an internationally competitive product. The keys to market penetration are the IV and oral bioavailability (enabling step-down therapy), the spectrum of activity including both Gram+ve and Gram-ve pathogens and the ultra-low spontaneous resistance frequency.

DNA supercoiling is regarded as 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.

Abgentis has identified an opportunity to improve an antibacterial that was marketed but was uncompetitive. Compared to HTS and Lead Optimisation campaigns to create new chemical classes, re-engineering a marketed compound creates a low-risk, cost-effective and rapid programme and investment opportunity.

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