March 21, 2010 ─ (BRONX, NY) ─ Researchers at Albert
Einstein College of Medicine of Yeshiva University have found two
novel ways of killing the bacteria that cause tuberculosis (TB), a
disease responsible for an estimated two million deaths each year.
The findings, published in the March 21 online issue of Nature
Chemical Biology, 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," says William R. Jacobs, Jr., Ph.D., the
study's senior author and professor of microbiology &
immunology and of genetics at Einstein, as well as a Howard Hughes
Medical Institute investigator. "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."
Tuberculosis is caused by the bacterial species Mycobacterium
tuberculosis. In searching for a new Achilles' heel for M.
tuberculosis, Dr. 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," says Dr. Jacobs. "That's usually a very effective
way to kill bacteria, when you start damaging the DNA."
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,"
notes Dr. Jacobs. "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."
Dr. Jacobs adds that findings from this study could also enhance
treatment of diseases caused by other species of mycobacteria.
Leprosy, for example, which still occurs in the U.S. and other
countries, is caused by a mycobacterium related to TB. Treating
leprosy now involves using several different drugs, some of which
are also used to treat tuberculosis.
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