Research by K-RITH scientists has opened up possibilities for the development of new, better and faster ways to treat tuberculosis (TB).

In an article published in the academic journal Nature Communications, scientists for the first time characterise how the Mycobacterium tuberculosis electron transport chain (ETC) works in the presence of TB drugs which target its ETC.

ETCs are the pathways by which cells produce energy in the form of ATP (the energy carrying molecule), which is vital for survival. To do this research K-RITH scientists optimised an Extracellular Flux Analyser to study Mycobacterium tuberculosis (M.tb) – the bacterium which causes TB. The instrument is normally used to study illnesses like cancer and diabetes using mammalian cell lines. It measures the oxygen consumption rate, a measure of how well the ETC and therefore energy production works, of the cells – or bacteria.

Scientists found that M.tb’s ETC functionally differs in surprising and important ways from those in mammalian cells; rapidly re-routing around the inhibition caused by the ETC targeting drugs and in doing so increasing cellular respiration.

Lead author Dr Dirk Lamprecht uses a car crash analogy to describe the process:

“Think of it as a highway; there was a crash and now there’s a pileup. That’s what happens if any of the components of the mammalian ETC is inhibited. What we’ve figured out is that M.tb has some mechanisms by which ‘traffic’ can be rerouted around the site of inhibition, or ‘crash’, to keep the ETC going. But, because the main way of producing energy has now been inhibited, back-up systems kick into gear; so it actually uses more oxygen than it would have normally. It’s counter-intuitive; inhibiting the ETC causes an increase in respiration. It’s totally the reverse of what you see in mammalian cells and hasn’t been yet shown to happen in other bacteria.”

Exploiting this metabolic response, the researchers combined leprosy drug clofazimine with new TB drugs bedaquiline (FDA approved) and Q203 (in clinical trials) – causing rapid killing in vitro and in a macrophage model. Importantly, the regime was non-toxic to mammalian cell lines. This raises some exciting possibilities.

“This proves it can be done; you can kill M.tb without killing the host cells by using three drugs that target its energy producing pathways,” says Lamprecht. “There are a whole lot of compounds that were shelved by pharmaceutical companies – because they weren’t going after the ‘right’ targets – that can now possibly be re-screened to see if they can be used safely in combination to effectively kill M.tb.”

It also opens new lines of investigation: instead of targeting the individual ETC components, researchers could potentially exploit the differences between the mammalian and M.tb energy producing pathways. “We’ve shown there are these differences; perhaps it’s within these differences that we can target M.tb energy metabolism safely.”

*Read the full article here.