New drug targets for tuberculosis identified
doi:10.1038/nindia.2016.5 Published online 18 January 2016
Researchers have identified 94 new TB drug targets in Mycobacterium tuberculosis, the organism that causes tuberculosis, using bioinformatics tools1. The new targets may lead to development of novel drugs, scientists at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad say.
"After further validation, some of these targets may lead to development of new medications for this major infectious disease," Kunchur Guruprasad, project leader at CCMB and corresponding author, told Nature India.
Though a cure for tuberculosis exists, increased resistance to known drugs has created an urgent need to identify new targets. Drug developers have used several methods to identify TB drug targets but CCMB's approach is different.
"The availability of protein sequences from several M. tuberculosis genome strains, bioinformatics tools for identifying homologous proteins, and computer programmes for modeling protein three-dimensional structures have made it possible to attempt the twin goals of predicting potential drug targets and drugs," Guruprasad said.
CCMB researchers used various bioinformatics tools to compare 92,325 protein sequences representing 23 M. tuberculosis genome strains with the known human protein sequences from the U.S. National Centre for Biotechnology Information database. This led to identification of 1, 478 ‘conserved’ M. tuberculosis proteins that are absent in humans. After analysing the protein–protein interaction networks of the ‘conserved’ proteins in the M. tuberculosis virulent genome strain H37Rv "we prioritised 140 proteins as potential TB targets," the authors report.
"Out of the 140 targets identified, 46 were previously known," Guruprasad said. "This increased the confidence in our prediction of the remaining 94 proteins as representing potential new TB targets."
Analysis of the structures and functions corresponding to the predicted TB drug targets indicated a range of proteins associated with around 70 diverse functions such as host cell invasion, virulence, maintenance of cell wall integrity, transcription, translation and protein export. Ten protein targets could be identified as being ‘druggable', meaning some known drugs (such as estradiol, methotrexate, sildenafil, rifampin, aliretinoin, trifluoperazine, tadalafil and troglitazone) could be effective against these targets.
"In future, as more drugs to treat various human diseases enter the market, it should be possible to identify whether any of them would also be useful for the treatment of TB," the authors report. "Our approach could be yet another way to identify potential drug targets for other infectious diseases," says Guruprasad.
But not everyone is that optimistic. "It is an elegant bioinformatic study, sort of building upon a number of individual data pieces," says Tanjore Balganesh, a TB expert and former head of Research at AstraZeneca in Bengaluru. "15 years ago we started with a lot of aplomb on predicting new TB drug targets but we had very few successes. We still do not understand why," he told Nature India. "Thus while predicting targets is an useful exercise converting them into reality is a nightmare."
1. Sridhar, S. et al. Comparative analyses of the proteins from Mycobacterium tuberculosis and human genomes: Identification of potential tuberculosis drug targets. 579, 69–74 (2016) doi:10.1016/j.gene.2015.12.054