New pathway for glucose production identified in TB bacteria might be good drug target

10 August 2015

M. tuberculosis, generated by Maximiliano Gutierrez from the Francis Crick Institute using scanning electron microscopy.

Image: M. tuberculosis, generated by Maximiliano Gutierrez from the Francis Crick Institute using scanning electron microscopy.

The production of glucose from non-carbohydrate sources fuels tuberculosis (TB) infection. This metabolic pathway, known as gluconeogenesis, might be a good drug target, according to new research from the Francis Crick Institute and Weill Cornell Medical College in New York, USA.

The team identified a redundant step, indicating a second unknown protein was acting in this TB pathway. Consistent with this proposal, deletion of the first, well known, enzyme had no effect in experimental infections, indicating that a second enzyme was acting as its back-up.

Dr Luiz Carvalho of the Crick explained: "Fatty acids are well accepted as one of the main food sources for the Mycobacterium tuberculosis, the pathogen that causes TB, during infection".

"The metabolic pathway known as gluconeogenesis is therefore essential for the synthesis of carbohydrate, nucleotides (the 'building blocks' of DNA and RNA) and several amino acids (which make up proteins)."

The team investigated an ezyme involved in gluconeogenesis called fructose 1,6 bisphosphate phosphatase (FBPase). Their research combined bacterial, genetic, microbiology and biochemical techniques with state-of-the-art screening of metabolism products and mouse infection experiments.

Unexpectedly they found that deleting the gene for FBPase didn't affect growth in fatty acids, indicating that either a new metabolic pathway or that an unknown enzyme was acting to convert fatty acids into glucose.

The researchers went on to discover a second FBPase (FBPase II) in  M. tuberculosis. Further work in mice showed that the genes for both FBPases needed to be deleted to reduce TB infection, providing strong evidence that gluconeogenesis is indeed an important metabolic pathway during TB infection.

Importantly, when both genes encoding FBPases are deleted, M. tuberculosis infection is cleared from the host, emphasising the importance of gluconeogensis during infection and its potential as a drug target.

Dr Carvalho said: "Our discovery provides important information for ongoing drug discovery efforts aimed at finding new compounds to treat human TB."

"Our study proves for the first time that gluconeogenesis is taking place during infection, and therefore indicates that ideal gluconeogenic inhibitors might be sought as new drugs. However we also demonstrate that due to redundancy, FBPase is not a good target in M. tuberculosis."

He added: "It is becoming increasingly important to confirm possible targets in drug discovery. Studies such as this, that provide strong indications that particular enzymes are not essential, are of great importance to rationally guide the selection of those targets that are worth pursuing."

The paper, Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in M. tuberculosis, is published in Nature Communications.

  • Research led by Dr Luiz Carvahlo from the Francis Crick Institute and Dr. Sabine Erht from Weill Cornell Medical College in New York, USA, provides the first evidence that the metabolic pathway through which glucose is produced from non-carbohydrate sources might be a good target for new tuberculosis (TB) treatments.
  • TB is an infectious bacterial disease that most commonly affects the lungs. It is transmitted via droplets from the throat and lungs of people with the active respiratory disease. In 2013, there were around 9 million new cases of TB and 1.5 million died from the disease.