NEW FINDING OFFERS HOPE OF MORE EFFECTIVE TREATMENT FOR TUBERCULOSIS
01 April 2000 - Washington University in St Louis

"Persistence is one of the hallmarks of this organism," says David G. Russell, Ph.D., senior author of the paper published in the Aug. 17 issue of Nature. "It 's what makes tuberculosis such a serious problem."

When the study was performed, Russell was a professor of molecular microbiology at the medical school. He now is professor and chair of microbiology and immunology at the College of Veterinary Medicine, Cornell University.

The tuberculosis bacterium, Mycobacterium tuberculosis, is the world's most deadly infectious organism, killing 3 million people each year. White blood cells called macrophages, which normally destroy harmful microbes, ingest the bacterium. But M. tuberculosis is able to survive and grow inside macrophages for years.

Russell and his colleagues suspected this was made possible in part by the glyoxylate shunt, a biochemical pathway that allows bacteria to use compounds containing only two carbon atoms as food. Isocitrate lyase is a key enzyme in this shunt.

To test this idea, collaborators John D. McKinney of The Rockefeller University and William R. Jacobs, Jr. of the Howard Hughes Medical Institute at Albert Einstein College of Medicine genetically deprived M. tuberculosis of the ability to make ICL. They then infected one group of mice with the mutant strain and a second group with the normal strain.

During the early, acute phase, both host groups developed the infection at the same rate. Later, however, the mutant bacteria were steadily eliminated while the normal strain persisted. Only the mice in the second group developed inflamed and enlarged lungs.

In another part of the study, researchers learned that M. tuberculosis produces ICL at a much greater rate in activated macrophages than in resting ones. The mutant bacterium also was much less able to survive inside activated macrophages than in resting macrophages, suggesting that M. tuberculosis must use the glyoxylate shunt to survive when macrophages become activated. "This is the first demonstration that a metabolic pathway of an infectious agent can be dictated by the immune status of a host," Russell notes.

Tuberculosis is chronic, physicians believe, because patients harbor bacteria in various metabolic states. "The drugs we now use against the disease hit only the rapidly multiplying bacteria," explains Russell. "They miss the vegetative ones. So ICL, which appears crucial to the survival of bacteria in the vegetative state, may make a good target for the development of therapeutic drugs."

Further collaboration with James C. Sacchettini at Texas A&M University has led to the recent solution of the 3-D structure of ICL combined with prototypes of inhibitors (published in Nature Structural Biology). Therefore, the development of specific inhibitors of ICL appears feasible and is the basis of an ongoing interaction with Glaxo Wellcome. Such drugs presumably could be used against M. tuberculosis without harming patients, because humans appear to lack the glyoxylate shunt pathway.

McKinney JD, Honer zu Bentrup K, Munoz-Elias J, Miczak A, Chen B, Chang W-T, Swenson D, Sacchettini JC, Jacobs WR Jr, Russell DG. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature, Aug. 17, 2000

Sharma V, Sharma S, Honer zu Bentrup K, McKinney JD, Russell DG, Jacobs WR, and Sacchettini JC (2000). The structure of M. tuberculosis isocitrate lyase: A lynchpin to survival within the immune host. Nature Structural Biology. 7, 663-668

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