GlaxoSmithKline has signed a research agreement with the not-for-profit, public-private partnership, the Global Alliance for TB Drug Development, to co-develop four projects that may yield new anti-tuberculosis drugs.
The two parties will fund 25 scientists each at GSK's Tres Cantos facility in Spain, which undertakes research on two diseases of the developing world, TB and malaria.
The partnership hopes to find new drugs that will cut two to four-months off the current six to nine-month treatment times and find agents that have fewer drug interactions with antiretrovirals as patients are often co-infected with TB and HIV. "It is possible to get treatment times down to two months or less," says Dr Mel Spigelman, director of R&D at the TB Alliance.
One of projects will study pleuromutilins, a fungal-derived class of antibiotics, which inhibit bacterial protein synthesis (they bind to the bacterial transferase centre). In vitro studies have shown that pleuromutilins can inhibit the growth of the TB mycobacterium and they are already used for mycoplasmosis infections in pigs and poultry.
Two of the projects will focus on targets novel to mycobacteria: isocitrate lyase, which provides essential nutrients to the bacteria, and InhA, an enoyl-ACP reductase enzyme involved in the bacteria's fatty acid production.
The fourth project will involve GSK screening its antimicrobial libraries for novel anti-TB agents, including targets for inhibitors of DNA gyrase, peptide deformylase and analogues of quinolone electron transport inhibitors.
It is still uncertain how the TB mycobacterium undergoes drug resistance. It is mostly thought that it undergoes phenotypic resistance, where there may be a shift in its metabolism and it is no longer sensitive to antibiotics (its genome remains unchanged). Isocitrate lyase is one of the best leads on fighting phenotypic resistance, says Dr Spigelman. The enzyme is also up-regulated during infection of macrophages.
Dr Federico Gomez de Las Heras, director of GSK's diseases of the developing world programme, says the company expects to identify a candidate in the next two years that would go into the clinic from the partnership. If a product does come to market from the partnership, GSK has promised to sell it at preferential prices for developing countries.
Separately, the TB Alliance says that on a global basis six or seven products (none are GSK products) will enter the clinic this year. The most advanced products are the 4-quinolones, which are in Phase II clinical trials (an announcement will be made on this shortly).