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Researchers discover metabolic vulnerability in TB and potential drug target

Study led by Weill Cornell Medical College and published in the journal PNAS

Tuberculosis (TB) has been present in humans since ancient times. The origins of the disease date back to the first domestication of cattle, and skeletal remains show prehistoric humans (4,000 B.C.) had TB. Although relatively rare in the United States, it is the single leading bacterial cause of death worldwide. Approximately 8 million people are infected each year and 2 million people die from TB.

The cause of tuberculosis is Mycobacterium tuberculosis (Mtb), a slow-growing aerobic bacterium that divides every 16 to 20 hours. Scientists know that carbon metabolism plays a significant role in the ability of Mtb to replicate and persist in the body and that fatty acids are the major source of carbon and energy during infection. However, the specific enzymes required for the metabolism of fatty acids have not been completely defined.

New research conducted at Weill Cornell Medical College and published online in the Proceedings of the National Academy of Sciences (PNAS) sheds light on a previously unrecognized aspect of fatty acid metabolism that could potentially lead to new targets for drug therapy. A team led by Dr. Sabine Ehrt, professor of microbiology and immunology at Weill Cornell Medical College, reported that Mtb relies primarily on gluconeogenic substrates for in vivo growth and persistence, and that phosphoenolpyruvate carboxykinase (PEPCK) plays a pivotal role in the growth and survival of Mtb during infections in mice, making PEPCK a potential target for drugs that fight tuberculosis.

Dr. Ehrt and her colleagues found a way to silence the gene encoding PEPCK in Mtb during mouse infections to assess the importance of gluconeogenesis for Mtb's ability to maintain a chronic infection. According to Dr. Ehrt, "Silencing a gene when the pathogen is not or only slowly replicating, after an infection has established, is an important tool for studying diseases such as TB, which can be dormant for years only to become active again years later."

Dr. Ehrt, the lead author on the paper, conducts basic research on the pathogenesis of tuberculosis. She and her team investigate the role of the macrophage in the immune response to Mtb and the molecular mechanisms used by the pathogen to establish and maintain persistent infections. A goal of Dr. Ehrt's research is to validate novel drug targets that may facilitate the development of new therapies against active and chronic TB.

"Tuberculosis is very difficult to treat," says Dr. Erht. "It is especially challenging as the infection can lay dormant in the body even though there are no symptoms. We investigated the metabolic requirements of Mtb during acute and chronic infections and found that the gluconeogenic enzyme PEPCK is critical for both."

The study used a novel mass spectrometry-based metabolic profiling tool, developed at Weill Cornell (in collaboration with Agilent Technologies) by Dr. Kyu Rhee to biochemically examine Mtb carbon metabolism. The tool has provided the first direct insights into the metabolic architecture of Mtb. Dr. Rhee is a co-author and assistant professor of medicine, microbiology & immunology, and the Hearst Clinical Scholar in Microbiology & Infectious Diseases at Weill Cornell Medical College.

Dr. Ehrt hopes that her work will eventually lead to new drug therapies to treat tuberculosis. "Although the current treatments we have to treat Mtb are effective, the treatment times are too long and the regimens too complex. This leads to treatment failures, due to poor adherence and multidrug resistance. We need new, safer drugs that work faster to eliminate tuberculosis."

Additional co-authors include Weill Cornell's Drs. Dirk Schnappinger and Joeli Marrero, and Kevin Pethe, a researcher from the Novartis Institute for Tropical Diseases Pte Ltd. in Singapore.

The work was supported by the National Institutes of Health, a Bill and Melinda Gates Foundation Grand Challenges Exploration Grant, a Burroughs Wellcome Career Award in the Biomedical Sciences, and the William Randolph Hearst Foundation.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals.

Andrew Klein | EurekAlert!
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