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News

Shining sweetness, fluorescent sugars shed new light on future TB therapies

Austrian Science Fund (FWF) : 19 May, 2003  (Technical Article)
The discovery that fluorescent sugar molecules mark important enzymes of the tuberculosis bacillus will facilitate investigation of the potential importance of the enzymes for future tuberculosis therapies This insight is a gratifying 'by-product' of research at the Institute of Organic Chemistry at the Graz University of Technology. A project funded by the Austrian Science Fund encountered the fluorescent sugar molecules while analysing the mode of action of an existing TB therapy.
The fact that a useful tool for improving existing treatments and developing new ones was found in this way highlights the valuable role that can be played by independent research and creative scientists.

Whilst observing special sugar molecules (iminosugars) under a fluorescence microscope the Graz research team under Professor Arnold E. StŁtz noticed a helpful effect in some of the sugars. Those presenting certain lipoid groups emitted light. Professor StŁtz explains the potential applications in the search for TB therapies as follows: 'Some iminosugars attach themselves to an enzyme that is crucial to the viability of the tubercle bacillus and is involved in forming the cell wall. In conjunction with their fluorescent property this makes them excellent markers, 'position lights' for the enzyme so to sa, enabling us to target them for observation.' Thanks to the discovery, fluorescence intensity can be used to test the potential effectiveness of new substances in inhibiting the growth of the cell wall of the TB bacillus. The development of new TB drugs is an urgent matter because of the current spread of the disease, with between eight and 12 million new cases occurring every year.

The project supported by the FWF set out to investigate the iminosugars and their ability to inhibit the cell wall synthesis of the bacillus responsible for tuberculosis (Mycobacterium tuberculosis). The sugars are similar in structure to the most effective drug currently available, ethambutol, which also inhibits the formation of the cell wall. As they are chemically easy to modify, iminosugars present themselves as a research target, and a model for subsequent comparison with ethambutol.

By modifying the structures of iminosugars and ethambutol, the Graz team sought to determine whether the mode of action on the relevant enzymes could be improved. In the words of Professor StŁtz: 'We made 50 variants of the iminosugars and the ethambutol, and analysed the effect on binding to the enzyme. This enabled us to analyse the functioning of the enzyme and the medication more precisely, and make it easier to understand.' It emerged that, of all the variants tested, ethambutol was the most effective treatment. This was just as surprising for the researchers as the discovery of a 'by-product' the fluorescent iminosugar. The latter will speed up the future development of more powerful tuberculosis drugs.

The new president of the FWF, Professor Georg Wick, said of this unexpected success: 'Regardless of whether the original goal is achieved, good fundamental research is always of value to society, a fact convincingly demonstrated by Professor StŁtz's team. We shall continue to focus on supporting flexible scientists who look at their results with an open mind. This is how basic research can generate maximum outputs and strengthen Austria's knowledge base.'
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