LEAD SERIES DEVELOPMENT & OPTIMISATION OF A NEW DRUG AGAINST ACTIVE AND LATENT TUBERCULOSIS

According to the most recent estimates, TB killed 1.7 million people in 2009 (approximately a death every 20seconds). Treatment for TB relies on drugs developed some 40 years ago. Unfortunately these drugs are not very good as they require long treatment regimes (6-9 months) and often they do not work due to the ability of the TB bug to develop resistance. Using a novel strategy we propose to develop a new drug that will be able to kill all of the TB bugs quickly including the resistant ones. To develop this drug we have partnered up with industry (GSK pharmaceuticals) and will use industry-like development and management methods. If we succeed in this 2 year project, we are confident that we can secure future funding from the TB Alliance so that we can eventually register our new drug within the next five or six years.

A major failure of current tuberculosis (TB) therapies is that they predominantly target replicating Mycobacterium tuberculosis (Mtb) but are unable to sterilize slow growing (dormant) Mtb, leading to protracted treatment regimes and the development of drug resistance. We propose to generate a new drug against TB that is able to mitigate the shortcomings of current therapies, leading to improved treatment outcomes. Our strategy is to target the Mtb respiratory chain, specifically NADH:menaquinone oxidoreductase (ndh). This target is essential for the survival of replicating, dormant and drug resistant Mtb, and it is absent in humans. Over the past 2 years we have successfully progressed from target validation/hit identification to the discovery of novel potent (nM) inhibitors of ndh with corresponding potent (nM) in vitro sterilization activity against replicating and dormant Mtb. This proposed schedule of work is to advance these early leads through to late lead development and optimization in readiness for candidate selection.