TB Alliance Portfolio
September 2010

Background

Quinolone antibiotics, such as moxifloxacin, are highly active against TB, with the potential to significantly reduce the duration of TB treatment. (Moxifloxacin is a TB Alliance/Bayer drug candidate currently in clinical trials.) Quinolones target and inhibit the enzyme DNA gyrase, the only type II topoisomerase so far identified in the Mycobacterium tuberculosis (M.tb) genome. Such inhibition results in mycobactericidal cell killing. DNA gyrase is therefore a highly validated target for anti-tubercular drug discovery.

Compounds that inhibit DNA gyrase are also active against non-replicating, persistent mycobacteria, believed to be important for shortening the duration of TB drug therapy. A novel inhibitor of the enzyme would also be effective against multidrug-resistant (MDR) TB, and could be effective against quinolone-resistant M.tb.

The TB Alliance is working with GlaxoSmithKline (GSK) to identify a novel DNA gyrase inhibitor that is outside of the quinolone class. GSK has already developed several novel gyrase inhibitors that bind outside the gyrase region responsible for quinolone resistance, and therefore lack cross-resistance with quinolones. Some of these compounds have already been tested in vitro and in vivo and found to have potent activity and efficacy against M.tb.

Project Status

Progress to Date

The mycobacterial gyrase inhibitor program is now in the lead optimization stage. Researchers at GSK have identified a promising lead series after extensive screening against both replicating and non-replicating Mycobacterium tuberculosis (M.tb). In vivo proof-of-principle studies in a mouse TB model have been conducted.

Optimization of the identified lead series has already improved the in vitro potency against M.tb. and optimization of the efficacy and pharmacokinetic and toxicological profiles is ongoing.

Next Steps

Ongoing lead optimization is aimed at continued improvement of the potency, efficacy safety and pharmacokinetics. Compounds that exhibit superior profiles against M.tb will be advanced into preclinical development.

Lead Team

The TB Alliance has partnered with GlaxoSmithKline (GSK) on a number of projects, to develop medicines that will shorten the duration of TB therapy. A steering committee, comprised of representatives from both organizations, is responsible for project decisions and for monitoring the collaboration's progress.

Over the last two decades, GSK has invested heavily in anti-bacterial research and development. At the same time, GSK maintains a drug discovery unit focused exclusively on diseases of the developing world (DDW). These factors, along with GSK's extensive network of partners and advantages of scale, make the company an invaluable partner in the search for a faster, better TB drug regimen.

The TB Alliance works directly with the GSK DDW unit housed at a facility in Tres Cantos, Spain. The unit's scientific staff members are experts in understanding disease targets and identifying novel drug candidates for further development. Specialties include chemistry, biology and other drug discovery disciplines. The Tres Cantos group is also fully integrated with GSK's general research and development programs, ensuring their access to all necessary technologies and resources.

Early in 2008, the TB Alliance and GSK agreed to renew their partnership through 2011.

Supporting Materials

Bibliography