Finding Tuberculosis' Achilles Heel

Antibiotic-resistant Mycobacterium tuberculosis has become a huge public health issue around the world. As a result, the search for new drugs that combat this bacterium and treat tuberculosis is ever more urgent.


Huilin Li, a biophysicist at Brookhaven National Laboratory and associate professor of biochemistry at Stony Brook University, does detailed structural studies of an intracellular component of the tuberculosis bacterium – the proteosome that breaks down damaged proteins within the cell – and found a difference that has surprised scientists.


Proteosomes exist in all living cells. The fact that proteosomes don’t vary much between simple one-celled organisms and more complicated plants and animals generally means that their function is crucial to cell health and survival. Not only is it a surprise to find that the mycobacterium’s proteosome is quite different from those found in other organisms, it is also something that might be exploited to combat the disease-causing organism.


Working in tandem with researchers from Weill Cornell Medical College, who screened thousands of compounds that might bind with mycobacterium – but not human -- proteosomes, Li expanded his structural studies to investigate precisely how the inhibitory molecules interacted.


"Moreover, proteosomes are so big that Li's group had to make extra effort to determine their atomic structure with high precision. “We needed a really high resolution,” he says. To achieve a meaningful picture of an inhibitor binding to the Mycobacterium proteosome – at a 2.4 Angstrom resolution – took three years of careful study and the analytic power of Brookhaven’s National Synchrotron Light Source facility. The results were published in the premiere scientific journal Nature."


Other aspects of the tuberculosis pathogen’s proteosome await Li’s study. “My part is very basic science and we’re continuing to work on that,” he says. “The more we know, the better we can take advantage of the difference.”


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