A group of Indian researchers have deciphered the mechanism underlying high-level streptomycin resistance associated with three novel missense mutants including S70R, T146M, and R187M
Hyderabad, February 25: Tuberculosis (TB) is one of the 10 main reasons for death around the world and Multidrug-resistant Tuberculosis (MDR-TB), which is a type of tuberculosis caused by bacteria resistant to multiple drugs, remains a public health crisis all around the world.
Now a group of Indian researchers have deciphered the mechanism underlying high-level streptomycin resistance associated with three novel missense mutants including S70R, T146M, and R187M.
Streptomycin (STR) was the first antibiotic used for the treatment of tuberculosis and it blocks the protein synthesis by binding to the bacterial ribosome, resulting in bacterial death. It is well-known fact that mutation in the gene encoding 7-methylguanosine (m7G) methyltransferase enzyme (gidB) specific for the 16S rRNA is one of the reasons for Streptomycin resistance.
For finding mechanism, researchers performed molecular dynamics analyses, which suggested that the structure distortion in the binding pocket of gidB mutants modulate S-Adenosyl-L-methionine (SAM) binding affinity. At the structural level, these conformational changes bring a substantial decrease in the number of residues involved in hydrogen bonding and dramatically reduce the thermodynamic stability of mutant gidB–SAM complexes.
“We are in process of identifying potential inhibitors against crucial Mycobacterium tuberculosis targets using high-throughput virtual screening approach and use it for drug repurposing,” said Dr. Bharati Pandey.
Global reports of increasing multidrug-resistant TB cases proves that we are moving towards antibiotic crisis and there is an immense need of research into the mechanism of drug resistance. Drug resistance poses a challenge that requires advancement in diagnostics, surveillance, and therapeutic methods. This study will pave way toward design and development of potent anti-TB agents.
“In future, we plan to validate the potential inhibitors in-vitro and in-vivo which will reduce the costs of new drug development” added Dr. Bharati.
The research team included Dr. Bharati Pandey, Sukriti Goyal, Dr. Salma Jamal, Aditi Singh, Dr. Abhinav Grover from JNU, Dr. Sonam Grover from IIT Delhi, and Prof Jagdeep Kaur from Panjab University.
Prof Jagdeep Kaur’s laboratory is focused on molecular characterization of lipase enzymes from Bacillus sp. and Mycobacterium sp. and Dr. Abhinav Grover’s laboratory works on various biological problems such as the structure and biochemical properties of protein aggregation, molecular mechanism underlying drug resistance using extensive Molecular Dynamics (MD) simulations, Machine Learning approaches towards identification of novel genes.
The work was supported by University Grants Commission (UGC) for Dr. D.S. Kothari Post-Doctoral Fellowship and Faculty Recharge Position and Jawaharlal Nehru University, New Delhi.