Balasubramani G L
Jawaharlal Nehru University, India
Title: Drug repurposing approach to identify novel inhibitors for targeting DNA gyrase in Mycobacterium tuberculosis: insights into mechanism and drug action
Biography
Biography: Balasubramani G L
Abstract
Drug repurposing has gained momentum globally and become an alternative avenue for drug discovery. Though tuberculosis (TB) can be cured with the use of currently available anti-tubercular drugs, emergence of drug resistant strains of Mycobacterium tuberculosis H37Rv (Mtb) and the huge death toll globally, together necessitate urgently newer and effective drugs for TB. To address this problem, we screened FDA-approved drugs by virtual screening and binding free energy calculations to identify novel inhibitors that target two active sites of Mtb DNA gyrase (i) dimer interface of gyraseA subunit, (ii) a active site region of ATP binding (N-terminal domain) pocket on gyrase B subunit overlapping the site targeted by coumarin drugs. Here, we identified total of 4 compounds tightly binds to ATPase binding pocket of N-terminal domain of gyrase B. Results obtained from biochemical and biophysical studies shows strong binding of screened compounds and inhibits gyrase catalytic cycle. Our evidence strongly suggests that these compounds bind to the N-terminal domain of gyrase B. Furthermore, we performed drug susceptibility test using screened compounds on Mtb and showed less MICs as compared to reported drugs. This finding indicates all the identified compounds represents potential scaffolds for further optimization of novel antibacterial agents that can act on drug-resistant strains.