Antifungal drug kills TB bug

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Antifungal drug kills TB bug

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Tuberculosis Treatment

Scientists hoping to find new treatments for one of the world's most

deadly infectious diseases (Tuberculosis) 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 tuberculosis 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 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 tuberculosis capital of Europe, although most large

cities here and in North America have seen rapid increases in the

number of tuberculosis infections. However, the problem is most

acute in Africa and Asia where HIV/AIDS is also most prolific and a

shortage of traditional tuberculosis 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 tuberculosis 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

tuberculosis bacterium, and also that they bind very tightly to a

number of the TB P450 enzymes that we have isolated – inactivating

their function. "