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This Week in TB R&D – 1 June 2010


31 May 2010
by Working Group

Mary O'Reilly Science Illustration
credit: Mary O'Reilly Science Illustration

By Gerry Waters, Senior Director, Biology at the TB Alliance

A team of researchers led by Rainer Kalscheuer and Bill Jacobs at the Albert Einstein College of Medicine in New York recently published a paper titled “Self-poisoning of M. tuberculosis by targeting GlgE in an alpha-glucan pathway” in Nature Chemical Biology (2010, vol 6, pg 376) (*note: there is a fee to view the full paper). From the perspective of basic biology, the work represents the first time a biosynthetic pathway from the disaccharide trehalose to alpha-glucan, a polysaccharide with several potential functions, has been described. From a drug development point of view, an enzyme in the pathway, called GlgE, that elongates alpha-glucans by sequentially appending maltose to them, has a lot to commend it as a potential drug target.

First, GlgE provides a novel essential function in M. tuberculosis that has not been targeted by any drugs to date. As such, one would expect that there be no resistance in clinically important strains to inhibitors that may be developed in the future, a fact that makes it a good target for MDR and XDR-TB, in addition to its promise for treating drug-sensitive TB.

Second, based on elegant genetic experiments by Kalscheuer et al. it is clear that inhibition of GlgE will lead to a cidal, that is killing, effect and not merely a static, or no growth, effect in M. tuberculosis. This is clinically important, as one wants to kill the pathogen during drug treatment, not merely prevent its growth during the period that the patient is on the drug.

Third, the absence of GlgE function – in this work obtained through genetic manipulations, but in the future hopefully via inhibition of function with a drug – leads to accumulation of a toxic metabolite (maltose-1-phosphate) that seems to trigger more of its own production through upregulation of a suite of genes. This biological circuitry essentially creates a self-amplifying a death spiral that is triggered by loss of GlgE activity.

Although the above attributes are quite appealing from a drug development perspective, there is one clear challenge that the work of Kalscheuer et al. points out. It appears that the loss of GlgE function can be suppressed at a fairly high frequency by mutation of genes higher in the biosynthetic pathway that, in effect, prevent synthesis of the toxic metabolite that would normally be processed by GlgE. Thus, clinically, one would need to be cautious about emergence of resistance to a GlgE inhibitor.

The authors have clearly put GlgE on the radar screen for drug developers by showing that M. tuberculosis cannot grow in culture in the absence of GlgE function, and they have nicely shown that GlgE function is required to establish a TB infection in a mouse model. Overall, the work of Kalscheuer et al. beautifully illustrates how basic biology, including genetic dissection of metabolic pathways, can provide insights and potential avenues for future drug development.

What are some approaches which could be implemented that could reduce or prevent the emergence of resistance to a GlgE inhibitor? What are the caveats to these approaches? How would one address the potential role of GlgE in perpetuating an already established infection, which was not addressed in the Kalscheuer paper? Please share your thoughts and comments.

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