Researchers Ram Sagar Misra, Shailja Singh and Anand Ranganathan
NEW DELHI: Over the years, tuberculosis and malaria have developed resistance to most drugs, including antibiotics. That has been because most drug research focuses on targeting the pathogen — the TB bacteria or malaria parasite. Now, 22 researchers from JNU and BHU have shifted focus to the host cells which are infected and isolated a molecule that can help counter drug-resistant TB and malaria.
What they have done is use the pathogens’ defence mechanisms against itself. “Intracellular pathogens hijack essential host intracellular pathways to establish infection and spread,” the study said. For instance, after invading a host, tuberculosis-causing bacteria produce a toxin called TNT (tuberculosis necrotizing toxin) which kills immunity cells by depleting a cellular molecule, Nicotinamide Adenine Dinucleotide (NAD+), which aids metabolism. Too little NAD+ can kill immunity cells. But TNT can kill bacteria too.
So, the bacteria produce another chemical, a natural inhibitor for the toxin, called IFT (immunity factor for TNT). “We used inhibitor IFT to target toxins inside human cells. We prevented the death of these cells, were able to maintain NAD+ levels and reduce the growth TB bacteria,” said Anand Ranganathan, professor, special centre for molecular medicine, JNU, and co-author of the study published in Nature journal ‘Cell Death & Discovery’ on Thursday. Since malarial parasites operate in a similar manner, they tested the effect of NAD+ regulation on host cells. “We found that RBCs deprived of NAD+ don’t support invasion of malaria parasites,” said co-author Shailja Singh, associate professor, special centre for molecular medicine, JNU. Regulating this one molecule could open up ways to develop drugs. So, they started looking at ways to design and synthesise NAD+ “lookalikes”. “These compounds were screened against the activity of the TB toxin and for their inhibitory activity against both pathogens,” said co-author Ram Sagar Misra, associate professor, department of Chemistry, BHU. “They showed no toxicity towards host cell, establishing their potential as drug candidates.” Their next line of research will be to develop these compounds into drugs.