Metabolic vulnerability in tuberculosis and potential drug target discovered

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.