A collaborative study by researchers from Punjab University, Indian Institute of Technology (IIT) Delhi, Banasthali University, TERI University and the Jawaharlal Nehru University has identified how a particular gene in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), mutates to avoid the action of antibiotics. They have used computer simulations to study the behaviour of the mutated gene and understand how the mutation affects its interactions and binding with other molecules in the bacteria. The study also details the basis of resistance against the antibiotic streptomycin, observed in three different mutant strains of the bacteria.
Tuberculosis has become the world’s deadliest infectious disease with 1.4 million deaths in 2016 worldwide, one-third of which were in India alone. In spite of our prowess in science and technology, we have been unsuccessful in eradicating this disease because the causative bacterium is smarter than we thought. Mycobacterium has found a way to survive even the harshest drugs thrown at it by mutating itself and becoming drug resistant. So far, scientists have identified many genes which have high mutation rates. In this study, published in the Journal of Biomolecular Structure and Dynamics, the researchers have studied how mutations in one such gene, gidB, cause drug resistance towards the antibiotic streptomycin.
Streptomycin kills Mycobacterium by inhibiting the action of a particular ribosomal RNA called 16S rRNA, which is needed to synthesise proteins in bacteria. Streptomycin binds to a region on the 16S rRNA which contains a chemical group known as the methyl group. The gene gidB encodes for an enzyme which, upon binding to the molecule S-adenosyl methionine (SAM), adds this methyl group on the 16S rRNA. Without this action of gidB, streptomycin cannot inhibit the 16S rRNA and kill the bacteria, leading to streptomycin resistance.
In this study, the researchers chose mutations that resulted in changes in the amino acid sequence of gdiB and significantly impacted its binding to SAM. They showed that all the mutant versions of gidB have a significantly lower binding affinity for SAM due to a decrease in the size of the region where SAM binds. Their results also demonstrate that mutant gidBs are more flexible proteins which makes the gidB-SAM complex relatively unstable.
This study is one of the first to understand the molecular basis of streptomycin resistance in TB, caused by mutations in the gidB gene. This work will enable scientists to design and develop drugs and treatments for gidB resistant TB strains.