Scientists Discover How TB 'Develops Invincibility' Against Only Available Treatment For Killer Disease

Main Category: Tuberculosis
Also Included In: Biology / Biochemistry;  Respiratory / Asthma;  Infectious Diseases / Bacteria / Viruses
Article Date: 13 Mar 2008 - 1:00 PDT

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Scientists at the University of Leicester have uncovered a dramatic new twist in the battle against TB.

They have identified how the killer bacterium makes itself immune to a key component of the only effective treatment against the disease.

Earlier this month, a separate team of TB researchers at Leicester announced a new advance in their fight against the resurgence of TB in Britain. They isolated the molecular 'weapons' of the bacterium and are assessing ways to make the bacterium impotent.

Now, in new research published in the Journal of Biological Chemistry, another team from the Departments of Biochemistry and Chemistry at the University has shown how the TB bacteria becomes resistant to one of the only available treatments for the killer disease.

Dr Peter Moody of the Biochemistry Department said: "Isoniazid is a pro-drug that an enzyme in the deadly bacteria itself makes active."

"Using the technique of protein crystallography and the incredibly bright X-ray source of the European Synchrotron at Grenoble, my team and that of Professor Emma Raven of the Chemistry Department at Leicester along with Dr Katherine Brown of Imperial College have shown how the pro-drug binds to two very similar enzymes - and from this we can see how mutations in the bacterial enzyme protect it from the treatment."

This is the first time anyone has seen the way the pro-drug binds to activating enzymes.

Dr Moody said: "Drug-resistant forms of TB are approaching 10% of the 8000 cases a year in the UK, so understanding how this works is very important."

The researchers hope that this new understanding will help drug companies devise treatments for the resistant strains.

The study, funded by BBSRC, is published this week in the Journal of Biological Chemistry*.

Dr Moody added: "Unfortunately, development of the UK synchrotron source (Diamond) is under threat because of the shortfall in funding, which could limit our ability to do this sort of fundamental medical research in the future".

*The Tuberculosis Prodrug Isoniazid Bound to Activating Peroxidases
Clive Metcalfe, Isabel K. Macdonald, Emma J. Murphy, Katherine A. Brown, Emma Lloyd Raven, and Peter C. E. Moody
J. Biol. Chem., Vol. 283, Issue 10, 6193-6200, March, 2008

University Of Leicester

- A member of the 1994 Group of universities that share a commitment to research excellence, high quality teaching and an outstanding student experience.

- Ranked top for student satisfaction in England (jointly with Oxford) among mainstream universities (average score of 4.4 out of 5 for overall satisfaction)
- Ranked as a Top 20 university by The Sunday Times University Guide, The Guardian University Guide and the UK Good University Guide
- One of just 23 UK universities to feature in world's top 200- Shanghai Jiao Tong International Index, 2005-07.
- Ranked in top 200 world universities by the THES (Times Higher Education Supplement)
- Short listed University of the Year in 2007 by The Sunday Times and Short listed Higher Education Institution of the Year - THES awards 2005 and 2006
- Ranked top 10 in England for research impact by The Guardian
- Students' Union of the Year award 2005, short listed 2006 and 2007

Founded in 1921, the University of Leicester has 19,000 students from 136 countries. Teaching in 18 subject areas has been graded Excellent by the Quality Assurance Agency- including 14 successive scores - a consistent run of success matched by just one other UK University. Leicester is world renowned for the invention of DNA Fingerprinting by Professor Sir Alec Jeffreys and houses Europe's biggest academic Space Research Centre. 90% of staff are actively engaged in high quality research and 13 subject areas have been awarded the highest rating of 5* and 5 for research quality, demonstrating excellence at an international level. The University's research grant income places it among the top 20 UK research universities. The University employs over 3,000 people, has an annual turnover of £184m, covers an estate of 94 hectares and is engaged in a £300m investment programme- among the biggest of any UK university.

University Of Leicester