The bacterium that causes TB infects one third of the global population and kills up to 3 million people a year. The pathogen's success secret is that it can persist undetected in the lungs for decades. Now a team of researchers has discovered a vulnerability that suggests new ways to fight against this resilient bug.
When Mycobacterium tuberculosis initially infects a person, it flourished for a few weeks until the immune system marshals its defenses. The two then reach a dead end. The pathogen population will not increase, but the immune system can not get rid of already nestled bacteria in a class of immune cells called macrophages
During this so-called latent phase - which may last for decades - the bacterium is stuck with a restricted diet: It feeds carbon from lipids by a route called the glyoxylate shunt, which is present in bacteria and plants, but not humans. This makes the path of an attractive drug target, said John McKinney of Rockefeller University in New York, because there may be fewer side effects.
McKinney and colleagues investigated this way for a weak point. Now they have discovered that levels of an enzyme called isocitrate lyase (ICL), which is essential for this route are high in M. tuberculosis during its latent phase. To learn how the enzyme they created a knockout M. tuberculosis , which does not have ICL. These modified bacteria were cleared by the immune system in mice, the team reports in the August 17 issue of Nature .
"One of the things we do not understand is how M. Tuberculosis can sit in the tissues for years, even decades," says Jo Colston, an expert on microbial pathogenesis at the National Institute for medical research in London who was not involved in the study. "clearly, if you can knock a protein that allows [the bacterium] to survive, which represents a potential therapeutic target. "
McKinney and his colleagues are already looking for such compounds. In a second publication in the August issue Nature Structural Biology they and crystallographer James Sacchettini of Texas A & M University in College Station describe the protein structure of ICL. They also identified two compounds that stifle the active end of ICL and stop the enzyme, which can starve tuberculosis while he hides in macrophages.
Related Sites
John McKinney laboratory
homepage James Sacchettini
TB information Organization World health
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