TB drug discovery to receive major boost

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TB drug development is to receive a major injection of cash and expertise, the Global Alliance for TB Drug Development announced yesterday. The Alliance, which is funded by the Bill and Melinda Gates Foundation, the Rockefeller Foundation, the Dutch government and USAID, is launching a research partnership with GlaxoSmithKline’s Diseases of the Developing World programme to bring six or seven new drugs targeting novel steps in the life cycle of mycobacterium tuberculosis. Human studies on some of these compounds could begin during 2005.

“The TB drug pipeline has been transformed in the past two or three years,” said Dr Mel Spigelman of the Global Alliance for TB Drug Discovery in a press briefing yesterday. “We have six or seven new drugs that could go into human trials this year, which is a revolutionary development in the TB field.”

TB treatment has remained static for many years, and drug resistance is a major problem in many parts of the world, especially the states of the former Soviet Union. TB regimens are lengthy and cumbersome to administer, with an induction phase of two to three months of daily directly observed treatment, followed by a continuation phase of up to six months. Treatment of latent TB may last for up to one year. Discontinuation in all phases due to non-adherence or poor tolerability is high, and is a major contributor to the emergence of multi-drug resistance. Multi-drug resistant TB may require the use of five or six drugs for at least one year.

Glossary

protein

A substance which forms the structure of most cells and enzymes.

latent TB

A form of TB that is not active. Persons with latent TB are infected with M. tuberculosis but do not have any symptoms and they cannot spread TB infection to others. Only specific tests will tell if anyone has latent TB. Treatment for latent TB is recommended in people living with HIV. 

isoniazid

An antibiotic that works by stopping the growth of bacteria. It is used with other medications to treat active tuberculosis (TB) infections, and on its own to prevent active TB in people who may be infected with the bacteria without showing any symptoms (latent TB). 

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

tolerability

Term used to indicate how well a particular drug is tolerated when taken by people at the usual dosage. Good tolerability means that drug side-effects do not cause people to stop using the drug.

The Global Alliance’s goal is to develop an entirely new regimen that will shorten and simplify current TB treatment. There have been no new TB drugs introduced for over 40 years.

The research programme is seeking new targets and products to interfere with m.TB replication. These include:

 

  • pleuromutilins, a class of drugs not cross-resistant with any existing antibiotics, that interfere with bacterial protein synthesis and inhibit m.TB growth in the test tube.
  • isocitrate lyase (lcl), a protein that must be present for TB infection to persist in macrophages. Targeting this site may reduce the amount of time that continuation phase treatment must last for, and might also be useful in the treatment of latent TB infection.
  • INHA, a protein involved in fatty acid synthesis, is already the target for isoniazid, one of the mainstays of current TB treatment. However, isoniazid must be activated before it can inhibit INHA. “Our idea is to bypass that step and directly inhibit INHA,” explained Dr David Pompliano of GlaxoSmithKline.
  • GlaxoSmithKline will also screen its vast library of antimicrobials to find novel compounds that can kill m.TB.

 

TB is the most common opportunistic infection in HIV-positive individuals in developing countries, and its treatment is complicated by interactions between rifampicin, an essential component of anti-TB regimens, and the antiretrovirals nevirapine and efavirenz, either of which is recommended as the mainstay of anti-HIV treatment.

“We desperately need new drugs for TB that do not interact with first-line antiretrovirals,” said Mark Harrington of the Treatment Action Group, which has just launched funded by the Gates Foundation designed to increase advocacy for a joint approach to TB and HIV in the developing world.

“Early testing of drug interactions will be needed.”

The drug discovery project will be led by a joint academic-industry steering committee, and will be based at a GlaxoSmithKline research site in Spain. The Global Alliance is to provide support for 25 scientists who will work exclusively on TB drug discovery. GlaxoSmithKline has agreed that any discoveries resulting from the partnership will be affordable and accessible to those most in need.