MRC National Institute for Medical Research, London
Science for Health
New anti-tuberculosis agents
01 September 2009
There is an urgent need to develop new anti-tuberculosis drugs, highlighted by the ongoing rise in tuberculosis (TB) cases worldwide. One worrying factor in the current TB problem is the prevalence of multi-drug resistant (MDR) strains, which emerged as a threat to TB control more than 10 years ago. Despite ongoing attempts to control the worldwide problem, the situation appears to have escalated further. Mycobacterium tuberculosis strains resistant not only to the front-line drugs isoniazid and rifampicin, but also to an increasing number of second-line drugs, are becoming more common. These strains, termed extensively drug resistant (XDR) TB, are virtually untreatable using current therapeutics and, without the strengthening of the current TB control measures combined with a drive to introduce new anti-tuberculosis drugs, the situation is only set to worsen.
Kathryn Lougheed, working with Roger Buxton in Douglas Young's group in NIMR's Division of Mycobacterial Research, has collaborated with the Drug Discovery Group at MRC Technology to screen a large number of substances for anti-tubercular activity. A library of known drugs and pharmacologically active compounds, for which there has already been extensive research investigating their suitability and safety as human therapeutics, has been screened against Mycobacterium tuberculosis. A medium-throughput assay using the Alamar Blue reagent was set up to identify novel inhibitors of M. tuberculosis. Of the 1514 compounds screened, 53 were demonstrated to possess inhibitory properties against M. tuberculosis at a concentration of 5 µM or below. Of these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. It was demonstrated that all five were active against intracellular M. tuberculosis in a macrophage model of infection.
The anti-tuberculosis agents identified by Kathryn in this screen represent promising new scaffolds on which future drug development efforts can be focused. The screening of a number of additional libraries is also being planned. It is hoped that, through the screening of less well characterized and diverse compounds, it will be possible to identify additional scaffolds for future drug development.
Roger Buxton
Original Article
The research findings are published in full in:
Kathryn E.A. Lougheed, Debra L. Taylor, Simon A. Osborne, Justin S. Bryans and Roger S. Buxton (2009) New anti-tuberculosis agents amongst known drugs Tuberculosis, Epub ahead of print PubMed abstract
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