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Mycobacterium: Death by sugar

Functional Glycomics (15 April 2010) | doi:10.1038/fg.2010.15

A sugar-processing enzyme may provide a new therapeutic target for tuberculosis.

Mary O'Reilly Science Illustration

Despite vaccinations, screening, and antibiotics, tuberculosis remains the most deadly of bacterial infections. This global burden is due in part to the rise of drug-resistant strains of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. However, the development of new treatment options requires a better understanding of this pathogen and how it causes disease. In Nature Chemical Biology, William Jacobs and colleagues propose a new approach to destroying tuberculosis – by manipulating the bacteria's own metabolic pathways.

In Mycobacterium, cell wall and capsule components are generated through a four-step pathway in which the sugar trehalose is converted to α-glucan. Each step is catalyzed be a different enzyme. One of these, GlgE, is a maltosyltransferase that converts the intermediate compound maltose 1-phosphate (M1P) to α-glucan. Since the authors were unable to directly delete the GlgE gene in wildtype M. tuberculosis, they hypothesized that the enzyme is required for bacterial survival. To further examine this possibility, they used a back-door method to generate a GlgE-deficient mutant strain. By deleting GlgE in a mutant M. tuberculosis strain already lacking TreS, the first enzyme in the trehalose-converting pathway, live bacteria could be obtained. Then TreS was re-introduced on a plasmid in the presence of an inhibitor. With removal of the TreS inhibitor, a surrogate GlgE knockout strain was born.

The GlgE surrogate knockout strain was then used to infect mice. Without the enzyme, the bacteria died rapidly in vivo, suggesting that the GlgE-mediated trehalose pathway is necessary for growth in the host. Since the enzyme wasn't present to convert M1P to α-glucan, the intermediate sugar accumulated to lethal concentrations in the bacteria. The basis for M1P toxicity was revealed by global gene expression analyses: excessive M1P damages bacterial DNA and leads to breakdown of cellular respiratory mechanisms.

GlgE is absolutely required for M. tuberculosis survival. However, some bacteria were able to survive these experiments, probably by circumventing M1P accumulation with loss-of-function mutations in the TreS gene or another enzyme in the pathway. Given that survival of even a few bacteria limits the value of GlgE as a drug target, the authors also explored another pathway that M. tuberculosis uses to generate α-glucan. They found that one of the enzymes in this secondary pathway, the glucosyltransferase Rv3032, could not be inactivated in the mutant M. tuberculosis strain lacking TreS, demonstrating that these pathways are jointly essential.

This timely study demonstrates a two-pronged approach for battling tuberculosis. By inactivating both GlgE and Rv3032, M. tuberculosis bacteria are unable to survive and the chance of selecting for resistant bugs is negligible. Furthermore, as neither humans nor beneficial gut bacteria express GlgE homologues, the side effects of anti-GlgE treatment would most likely be minimal. These results present a new understanding of the molecular mechanisms that drive bacterial pathogenesis and survival, thus providing important clues in the hunt for new M. tuberculosis drug targets.

Heather Buschman

Original research papers

  1. Kalscheuer, R. et al. Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an a-glucan pathway. Nature Chem. Bio. (published online 21 March 2010) doi:10.1038/NCHEMBIO.340 | Article |