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Two novel ways to kill TB discovered | Scientists have discovered two novel ways of killing the bacteria that cause tuberculosis (TB).
According to researchers at Albert Einstein College of Medicine of Yeshiva University
, their findings could lead to a potent TB therapy that would also prevent resistant
TB strains from developing. "This approach is totally different from the way any
other anti-TB drug works. In the past few years, extremely drug resistant strains
of TB have arisen that can't be eliminated by any drugs, so new strategies for
attacking TB are urgently needed," said William R. Jacobs, Jr., the study's senior
author and professor of microbiology & immunology and of genetics at Einstein,
as well as a Howard Hughes Medical Institute investigator. Tuberculosis is caused
by the bacterial species Mycobacterium tuberculosis. In searching for a new Achilles'
heel for M. tuberculosis, Jacobs and colleagues focused on an enzyme called GlgE.
Previous research had suggested that GlgE might be essential for the growth of
TB bacteria. GlgE would also be 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 (consisting of two glucose molecules) into longer
sugar molecules known as alpha glucans - building blocks that are essential for
maintaining bacterial structure and for making new microbes through cell division.
GlgE was the third of four enzymes involved in this pathway leading to alpha glucans
molecules. Sure enough, 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. "We were amazed when we knocked out GlgE that
we saw this DNA damage response. That's usually a very effective way to kill bacteria,
when you start damaging the DNA," Jacobs said. The researchers discovered a second
way of killing TB after observing a crucial connection between their novel alpha
glucan pathway and a second pathway that also synthesizes alpha glucans. When
the researchers knocked out one of the other enzymes in their novel pathway, the
pathway's shutdown didn't 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 what the researchers term synthetic
lethality: two inactivations that separately were nonlethal but together cause
bacterial death. "The bacteria that cause TB need to synthesize alpha glucans.
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," Jacobs said. Jacobs adds that findings from this study could
also enhance treatment of diseases caused by other species of mycobacteria. The
research has been published in the March 21 online issue of Nature Chemical Biology.
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