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.
The group's paper, "Self-Poisoning of Mycobacterium tuberculosis by targeting GlgE in an a-glucan pathway," appears in the March 21 online edition of Nature Chemical Biology. In addition to Dr. Jacobs, other Einstein researchers involved in the study were Rainer Kalscheuer, Ph.D., Brian Weinrick, Ph.D., and Karolin E. Biermann, M.S. Other researchers include Karl Syson and Stephen Bornemann, John Innes Centre; Zhen Liu and James C. Sacchettini, Texas A&M University; and Usha Veeraraghavan and Gurdyal Besra; University of Birmingham in the United Kingdom.
Albert Einstein College of Medicine has filed a patent application on the discoveries described in the paper.
About Albert Einstein College of Medicine of Yeshiva University
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2009-2010 academic year, Einstein is home to 722 M.D. students, 243 Ph.D. students, 128 students in the combined M.D./Ph.D. program, and approximately 350 postdoctoral research fellows. The College of Medicine has 2,775 full time faculty members located on the main campus and at its clinical affiliates. In 2009, Einstein received more than $155 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five medical centers in the Bronx, Manhattan and Long Island – which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein – the College of Medicine runs one of the largest post-graduate medical training programs in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit www.einstein.yu.edu
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