Drug Discovery Opinion

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (Mtb). TB is difficult to treat and the most commonly used antibiotics, rifampicin and isoniazid, need to be used for many months to eliminate the infection. The recent resurgence of TB, together with the emergence of drug-resistant strains of the bacterium, underscores the need for new treatments and researchers at Weill Cornell Medical College and the Novartis Institute for Tropical Diseases have identified a metabolic vulnerability in Mtb that could lead to new targets for drug therapy.

In vitro, Mtb is able to grow on a variety of carbon sources but fatty acids are believed to be the major source of carbon and energy for the bacterium during infection of a host. When bacterial metabolism is primarily fuelled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is known to be essential for growth but the role of gluconeogenesis in the pathogenesis of Mtb had not been explored. Using genetic analyses and ¹³C carbon tracing, the team were able to show that phosphoenolpyruvate carboxykinase (PEPCK) – the enzyme that catalyses the first committed step of gluconeogenesis – is essential for the growth of Mtb supported by fatty acids. PEPCK was shown to be needed for growth of Mtb both in isolated macrophages derived from the bone marrow of mice and in infected mice.

Mtb lacking PEPCK failed to replicate in mouse lungs and silencing PEPCK during the chronic phase resulted in clearance of the infection, showing that Mtb relies on gluconeogenesis throughout the course of the infection. The finding that PEPCK plays a pivotal role in the growth and persistence of Mtb during both acute and latent infections in mice – and that PEPCK depletion also attenuates Mtb in IFNγ-deficient mice – suggests that this enzyme is an attractive target for chemotherapy.

The study is published in PNAS.

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