Researchers have found two new ways to kill the bacteria that cause tuberculosis (TB). The findings, published in Nature Chemical Biology, could lead to a potent TB therapy that would prevent resistant TB strains from developing.
The researchers focused on the enzyme GlgE, which previous research suggested might be essential for the growth of TB bacteria and also an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut.
The GlgE research revealed a previously unknown enzymatic pathway by which TB bacteria convert the sugar trehalose into longer sugar molecules known as alpha glucans. When the researchers inhibited GlgE, the bacteria underwent “suicidal self-poisoning.” A sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.
Additionally, when the researchers knocked out one of the other enzymes in their novel pathway, the pathway’s shutdown did not kill the bacteria; similarly, inactivating an enzyme called Rv3032 in the second alpha glucan pathway failed to kill the microbes. But inactivating both of those enzymes caused synthetic lethality: two inactivations that separately were nonlethal but together caused bacterial death.
"The bacteria that cause TB need to synthesize alpha glucans," said William R. Jacobs, Jr, PhD, the study’s lead author and professor of microbiology and immunology, and of genetics at Albert Einstein College of Medicine of Yeshiva University. "And from the bacterial point of view, you can’t knock out both of these alpha glucan pathways simultaneously or you’re dead. So if we were to make drugs against GlgE and Rv3032, the combination would be extremely potent. And since TB bacteria need both of those alpha glucan pathways to live, it’s very unlikely that this combination therapy would leave behind surviving bacteria that could develop into resistant strains."