Latent tuberculosis (TB) may become treatable now that an enzyme has been discovered that helps Mycobacterium tuberculosis evade the body's defences and the effects of antibiotics, say researchers in the US.
TB infection can persist in a latent form for years because M tuberculosis hides inside macrophages and, during this time, the enzyme - isocitrate lyase (ICL) - allows it to metabolise nutrients, say Dr John McKinney (Howard Hughes medical institute, New York) and colleagues.
ICL is one of the bacterial enzymes that make up the "glyoxylate shunt", a system that allows latent bacteria to survive in an environment in which carbohydrates are limited but lipids are available (eg, in lung granulomas). The authors comment: "Poor activity against slow- or non-growing bacteria is thought to be why conventional drugs take so long to eradicate [M tuberculosis] infection. Therefore, our demonstration that ICL promotes persistence of infection by enhancing bacterial survival within inflammatory macrophages makes it an attractive new target for chemotherapy." ICL is not present in mammals, which means that inhibitors of the enzyme may be a "prime target" for drug development. The three-dimensional structure of ICL is already known, which should make development of these inhibitors easier, the researchers say.
McKinney et al developed a strain of M tuberculosis whose ICL did not function, and tested its ability to infect mice. They found that during the first two weeks of infection, the lack of ICL made no difference to the normal pattern of infection. However, from two weeks onwards, the number of mutant bacteria in the lungs decreased, which indicated that the organism was being cleared from the lungs. The researchers suggest that two weeks into the infection, there is a change in the environment that may require the bacterium to alter its diet from carbohydrates to lipids. This may coincide with the onset of host immunity to the bacterium (Nature 2000:406:735).
In an accompanying commentary, Dr William Bishai (Johns Hopkins university, Baltimore) says that one in three individuals worldwide have latent M tuberculosis infection, with a 5 to 10 per cent lifetime risk of progression to active disease (ibid, p683). "Our current arsenal of antituberculosis drugs, developed over 30 years ago, is plagued by low potency and high toxicity. But . . . it may become possible to identify potent agents that act against both active and latent M tuberculosis," he says.