Old Vaccine Hits TB Like A Blast From The Past

A vintage BCG vaccine developed in the 1920s may be due a comeback after researchers found it offers better protection against modern tuberculosis strains than the current BCG (Bacille Calmette-Guérin).

TB kills nearly two million people every year. The BCG vaccine is a live, non-pathogenic strain of Mycobacterium tuberculosis – the bacterium that causes TB. It is still given in some developing countries, where meningitis caused by the bacterium is a threat to children. However, BCG has lost favour with regard to preventing the most common form of TB, which affects the lungs.

Tests have shown it gives little protection in some countries, mainly because people’s immunity to wild, related bacteria also wipes out BCG. It was never offered routinely in the US, and many European countries have abandoned it, including the UK in 2005.

The problem could be that BCG was inadvertently made too harmless, researchers say.

Stewart Cole and colleagues at the Pasteur Institute in Paris, France – where BCG was first invented – analysed 10 BCG strains introduced between 1924 and 1989. The team found the vaccine has been steadily evolving, mainly to adapt to the nutrient broth it is grown in. “We’ve barely changed the way we make BCG since 1921,” Cole notes.

Source: University of Manchester
Date: March 12, 2007

Antifungal Drug Kills Tuberculosis Bug

Science Daily — Scientists hoping to find new treatments for one of the world's most deadly infectious diseases say drugs used to treat common fungal infections may provide the answer.

Tuberculosis, or TB, is a highly contagious disease of the lungs that was thought to have been virtually eliminated by the 1960s, but is now resurgent and kills nearly two million people worldwide every year. New infections are occurring at a rate of one per second.

Of equal concern is the dramatic rise in the incidence of new strains of TB that are resistant to traditional antibiotics. As a result, the World Health Organisation, the Bill Gates Foundation and the European Union have all launched initiatives to tackle the problem.

Now, biologists at The University of Manchester have shown that chemicals called azoles -- the active agent in many antifungal drugs -- kill the TB bacteria, and could be effective in tackling the emerging drug-resistant strains.

"TB is back with a vengeance with a third of the world's population currently infected," said Professor Andrew Munro, who led the research in Manchester's Faculty of Life Sciences.

"The bacterium survives the initial attack by the body's immune system and then lies dormant, usually in the lungs, waiting for any sign of weakness, such as a secondary infection. Its resurgence over the last 20 years has been closely associated with the AIDS epidemic, which destroys the human immune system and has allowed TB to get a grip once again."

London is the TB capital of Europe, although most large cities here and in North America have seen rapid increases in the number of TB infections. However, the problem is most acute in Africa and Asia where HIV/AIDS is also most prolific and a shortage of traditional TB medicines and problems with patient compliance has led to the emergence of drug-resistant strains of the disease.

"There were only ever a limited number of drugs that were effective against TB anyway," said Professor Munro, who is based in the University's £38 million Manchester Interdisciplinary Biocentre.

"People in places like India or Africa would be given antibiotics but often not in sufficient quantities to kill the bug completely; this is how resistant strains develop and these regions have become huge breeding grounds for these 'super strains'."

Funded by the EU's NM4TB (new medicines for tuberculosis) project, the Manchester team set about trying to find alternative drugs that could be used to treat these multi-drug resistant varieties of TB, known as MDR-TB.

"We knew that the TB bacterium was a clever organism, able to evade the human immune system and to survive long-term, sometimes unnoticed, in the body. We also realised that these peculiar features of the TB bacterium must mean that there are 'unusual' aspects of its composition and biochemistry that set it apart from most other bacteria and that could provide new targets for antibiotic drugs.

"When we began looking at the bug and its DNA content in more detail, we noticed it had some unusual characteristics. In particular, we noted the presence of a very large number of enzymes called P450s, which are usually associated with more complex organisms

. "In humans, P450s oxygenate molecules in the body and are essential for steroid metabolism; they are also prevalent in the liver where they help us detoxify and dispose of countless chemicals and toxins that enter our system. Most bacteria have few, if any, P450s but we discovered that the TB bacterium has 20 different types."

Even more exciting for the team was the knowledge that existing anti-fungal drugs already target P450s as a way to treat, for example, systemic and more superficial infections caused by fungi such as Candida albicans (the causative agent of thrush).

"The class of drugs called azoles are able to kill off fungal infections by blocking the actions of one of its P450s that is essential for maintaining the cell structure," said Professor Munro. "We were able to show in laboratory experiments that various types of these azole drugs were also very good at killing the TB bacterium, and also that they bind very tightly to a number of the TB P450 enzymes that we have isolated -- inactivating their function."

The research -- published in the Journal of Biological Chemistry -- offers the potential of a whole new approach to fighting the TB bug and has already attracted interest from one major pharmaceutical company.

According to the World Health Organisation:

Someone in the world is newly infected with TB every second.
Overall, one-third of the world's population is currently infected with TB.
5-10% of people infected with TB (but who are not infected with HIV) become sick or infectious at some time during their life. People with HIV and TB infection are much more likely to develop TB.
It is estimated that 1.7 million deaths resulted from TB in 2004.
TB is a leading cause of death among people who are HIV-positive, accounting for about 13% of AIDS deaths worldwide.

Note: This story has been adapted from a news release issued by University of Manchester.

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