A previously unrecognized aspect of fatty acid metabolism in tuberculosis (TB) that could potentially lead to new targets for drug therapy has been highlighted by scientists at Weill Cornell Medical College.
Led by Dr. Sabine Ehrt, the researchers said that Mtb-a slow-growing aerobic bacterium that causes TB-relies primarily on gluconeogenic substrates for in vivo growth and persistence.
In addition, they said 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.
The researchers 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.
"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," said Ehrt, the lead author on the paper.
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.
Ehrt aimed to validate novel drug targets that may facilitate the development of new therapies against active and chronic TB.
"Tuberculosis is very difficult to treat. 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," said Erht.
The study used a novel mass spectrometry-based metabolic profiling tool, developed at Weill Cornell by Dr. Kyu Rhee to biochemically examine Mtb carbon metabolism.
The tool has provided the first direct insights into the metabolic architecture of Mtb.
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," she said.
The study has been published online in the Proceedings of the National Academy of Sciences (PNAS).