IISc researchers find asthma drug effective in treating TB

We looked for drugs that target the arginine biosynthesis pathway that is essential for the survival of the TB bacteria, says Avadhesha Surolia (centre).  

A drug (Pranlukast) currently used for treating asthma has been found to be effective against tuberculosis, researchers from the Indian Institute of Science (IISc), Bengaluru, have found. Studies carried out in mice models found the drug to be effective in treating TB both when used alone and in combination with an anti-TB drug rifampicin. The results of the study have been published in EMBO Molecular Medicine.

Besides speeding up the process of drug discovery by repurposing an existing drug, the highlight of the study is the new approach adopted by researchers led by Prof. Avadhesha Surolia from the Molecular Biophysics Unit at IISc to zero in on the asthma drug. The drug uses a unique strategy to target the TB bacteria and is therefore quite unlikely to cause any adverse side-effects either to the human cells or the beneficial bacteria found in humans.

Most of the current anti-TB drugs target either the RNA synthesis (transcription) or cell-wall synthesis of the bacteria. “But we decided to look for drugs that target the arginine (an amino acid) biosynthesis pathway that is essential for the survival of the TB bacteria as well the pathogenesis [process by which the bacteria cause the disease],” says Prof. Surolia.

Many steps make up the arginine biosynthesis pathway and one of them involves an enzyme ArgJ (Ornithine acetyltransferase) which is essential for the survival and virulence of TB bacteria. The ArgJ enzyme is unique to TB bacteria and its counterpart neither exists in humans nor in the beneficial bacteria of human microbiome. This makes the ArgJ an exciting target for drug development and is very unlikely to cause any harmful side-effects in the human host.

To further reduce the chances of the chosen drug causing any side-effects, the researchers decided to target a unique site on the ArgJ enzyme that is not found in other proteins described so far. “If you target the active site in the enzyme, there is a possibility that the drug will target the same site in other biochemical reactions in the body,” explains Prof. Surolia.

Based on these conditions, the researchers carried out in silico computational modelling of all FDA-approved drugs that bind to the site. After screening 1,400 drugs, 34 were found to be binding to the site. “Of the 34, we tested 15 drugs for their ability to bind to the enzyme site, and two drugs — Pranlukast (anti-asthma drug) and Sorafenib (anti-cancer drug) — were found to have inhibitory action,” he says.

Effective drug

Both these drugs were tested in vitro and were found to be effective in curtailing the growth of TB bacteria. “The asthma drug was found to be more effective in curtailing the growth when used alone and in combination with other anti-TB drugs — rifampicin and isoniazid,” says Archita Mishra from IISc and first author of the paper. “The combination of asthma drug and the two anti-TB drugs was significantly better in killing the bacteria than the currently used first-line combination drugs — rifampicin, isoniazid and ethambutol.”

“Like the asthma drug, ethambutol is also a metabolic inhibitor. So replacing ethambutol with the asthma drug for the combination therapy would be a viable strategy,” Mishra adds.

Both the drugs were also able to kill the bacteria found inside the macrophages (white blood cells) without causing any harmful side-effects to the macrophages.

The potency of the asthma drug was much higher than expected. This would mean that lesser amount of the drug will be sufficient to kill the bacteria within the macrophages. The higher potency comes from the drug’s ability to counter the survival strategy of the TB bacteria. When bacteria infect the macrophages, they usually cause inflammation within the cells, which helps the bacteria multiply. The asthma drug was able to prevent the bacteria from causing inflammation thereby proving to be more potent in killing them.

“Since the drug targets the pathogen as well as the host pathway, it could potentially help in treating multidrug-resistant TB bacteria,” says Mishra. The researchers are already working in that direction.

Animal trials

Even in mice models, the drug was more effective in killing the TB bacteria both when used alone and in combination with rifampicin. There were fewer granulomas in the drug-treated mice. “Our studies show that ethambutol can be replaced with the asthma drug,” he says.

The researchers plan to test the drug on guinea pigs in a few months’ time. The efficacy will be tested by using it alone and in combination with rifampicin. “If we get encouraging results from guinea pig studies, we can straight away conduct Phase II trials in humans, as the safety of the drug is already proven,” says Prof. Surolia.