Double Mutants in DNA Gyrase Lead to Ofloxacin Resistance in Mycobacterium tuberculosis

作者：Pandey Bharati; Grover Sonam; Tyagi Chetna; Goyal Sukriti; Jamal Salma; Singh Aditi; Kaur Jagdeep; Grover Abhinav^*

来源：Journal of Cellular Biochemistry, 2017, 118(9): 2950-2957.

DOI：10.1002/jcb.25954

• MYCOBACTERIUM TUBERCULOSIS
• MOLECULAR DYNAMICS
• FLUOROQUINOLONES
• DNA GYRASE
• DOUBLE MUTANT

Fluoroquinolones are among the most important classes of highly effective antibacterial drugs, exhibiting wide range of activity to cure infectious diseases. Ofloxacin is second generation fluoroquinolone approved by FDA for the treatment of tuberculosis by selectively inhibiting DNA gyrase. However, the emergence of drug resistance owing to mutations in DNA gyrase poses intimidating challenge for the effective therapy of this drug. The double mutants GyrA(A90V)GyrB(D500N)and GyrA(A90V)GyrB(T539N) are reported to be implicated in conferring higher levels of OFX resistance. The present study was designed to unravel the molecular principles behind development of resistance by the bug against fluoroquinolones. Our results highlighted that polar interactions play critical role in the development of drug resistance and highlight the significant correlation between the free energy calculations predicted by MM-PBSA and stability of the ligand-bound complexes. Modifications at the OFX binding pocket due to amino acid substitution leads to fewer hydrogen bonds in mutants DNA gyrase-OFX complex, which determined the low susceptibility of the ligand in inhibiting the mutant protein. This study provides a structural rationale to the mutation-based resistance to ofloxacin and will pave way for development potent fluoroquinolone-based resistant-defiant drugs.

• 出版日期2017-9