University of Leicester eBulletin

TB Research Receives Funding Boost

June 2002
No 124

Researchers at the University of Leicester have received £105,882 from the EU as part of a cross-Europe consortium of researchers striving to find new treatments for tuberculosis (TB). The multi-disciplinary project (led by workers at the world famous Pasteur institute in Paris) involves Leicester-based research to define new anti-TB drug targets, with the long term aim of developing new drugs that have multiple target enzymes in the TB bacterium. In this way, it is hoped that drug-resistance will not develop.

The Leicester research team was the first in the UK to uncover new structures for TB cytochrome P450 (or P450) proteins, found in unusually large numbers in the TB bacterium.  P450 structures solved at Leicester have been the highest in terms of resolution and consequently researchers have been able to derive more accurate information from these proteins than ever before.

The University of Leicester is a growing centre of expertise on TB research, with several groups researching different aspects of TB biology, biochemistry and pharmacology. Dr Andrew Munro, who leads the research into structural and functional genomics of Mycobacterium tuberculosis, explained the importance of this research:

“Fifty years ago people thought TB was dying out, but it has made a dramatic comeback, fuelled by the spread of the AIDS virus. In the third world, AIDS is a major problem, and once people’s immune system fails, the most likely illness to take over will be TB. Also, in Africa people are not getting the drugs they need or are not compliant in taking available drugs.  There are some reasonably good antibiotic drugs for TB, but people need to take them properly and to complete courses. If they don’t, resistant bacteria are able to evolve, multiply and spread. This leads to the antibiotic becoming useless against the resistant strains. The World Health Organisation has recognised that this is a global catastrophe waiting to happen.

“As people realise that TB is developing resistance to traditional drugs, we have to find new antibiotics and new targets for these drugs.

“With traditional anti-TB drugs failing, the key question is how to identify new targets in the pathogenic bacterium. We have been working on this for 3-4 years, and our research received a big boost from Stewart Cole’s group at the Institut Pasteur, who in 1998 determined the genome sequence of Mycobacterium tuberculosis, the entire DNA make up of the bacterium.   This led us to consider what the complement of proteins (encoded by the DNA) may be that make TB different from other organisms and could thus provide new targets for drugs. Our angle of research is through a group of proteins, the cytochromes P450. The P450s appear to provide an excellent and unexpected group of targets in Mycobacterium tuberculosis.”

P450s are commonly used already as targets for drugs in the treatment of yeast and fungal infections, but similar drug strategies for TB were ignored due to the assumption that the P450s and the types of molecules they typically bind in the cell were absent from the pathogen. The fact that the genome sequence showed the TB bacterium contains so many P450 enzymes has been a revelation, and previous information from studies on yeast and fungi has given researchers into TB a lead on what sort of drugs can bind the P450s. They now need to determine the structures of the proteins and determine how effective these types of drugs, many of which are of the azole class (eg clotrimazole, fluconazole), are in inactivating TB P450s and preventing growth of the pathogen.

The fact that a similar drug may act against several P450s simultaneously may be a major advantage. Once new drugs have been identified that will bind to four or five critical P450s, the bacterium will have great difficulty in developing resistance, since this would require structural changes in several target P450s simultaneously. Thus, the “multi-hit” strategy may kill the pathogen before it can develop resistance to P450-inactivating drugs.  

“It’s going to be a long battle,” added Dr Munro. “We have to find the P450s that are vital to the TB cell. We are getting interest from GSK (GlaxoSmithKline) – one of the few drug companies to sponsor research into TB drugs, but the reticence of many pharmaceutical companies in taking the initiative means that we will have to do most of the research here.”

NOTE TO EDITORS: Further information is available from Dr Andrew Munro, Department of Biochemistry, University of Leicester, telephone +44 (0)116 252 3464, facsimile +44 (0)116 252 3630, email awm9@le.ac.uk.

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