Tuberculosis drug target’s structure to point to new therapies

Scientists have worked out the structure of a class of enzyme that has been genetically validated as a new drug target in Mycobacterium tuberculosis, a pathogenic bacterium which is responsible for 2 million tuberculosis deaths worldwide each year.

The scientists have been awarded over £500,000 by the Biotechnology and Biological Sciences Research Council (BBSRC) to work out how this enzyme works and is regulated, which will help in the development of new therapies against tuberculosis.

In 2010, research groups at both the John Innes Centre and the Albert Einstein College of Medicine of Yeshiva University (Einstein) in New York identified a new pathway in Mycobacterium tuberculosis that is responsible for producing a sugar polymer that the bacterium uses as an energy store and in its coat, to help evade the immune system.

Blocking one enzyme in this pathway, called GlgE, causes an intermediary molecule to build up, which is toxic to M. tuberculosis. This makes GlgE a potential target for drugs with a novel mode of action.

The GlgE pathway is found in many other bacteria, including Streptomyces coelicolor, which is a soil bacterium that has been extensively studied at the John Innes Centre and around the world because it produces a number of antibiotics.

Publishing in the Journal of Biological Chemistry, the John Innes Centre researchers solved the structure for GlgE, and showed that the S. coelicolor GlgE has the same catalytic properties as that in M. tuberculosis, even though S. coelicolor uses the sugar polymer only as an energy store.

The newly funded three-year project will use the information obtained from studying the structure of GlgE to work out how it functions.

Making precise, directed changes to GlgE will help understand how GlgE produces specific sugar polymer structures and how GlgE is regulated.

The configuration of the active site will also help medicinal chemists to optimise inhibitor molecules that could be developed into therapeutics.

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