Tuberculosis (TB) is contagious in nature and immunocompromised patients have a higher probability of developing TB. The occurrence of drug resistance, has led to serious health concerns in the management of TB. In order to combat resistant tuberculosis there is an urgent need of identifying new drug targets and new drug combinations for the effective management and reduction in the duration of TB treatment. Targeting DNA gyrase that is involved in bacterial replication cycle, provides one rationale approach. Various fluoroquinolone based drugs have shown promising effect against DNA gyrase enzyme and in turn were successful in combat against MDR TB. However, GyrA domain mutations based resistance towards fluoroquinolones has put a question mark over current therapies for tuberculosis. Fluoroquinolones target GyrA domain of bacterial DNA gyrase therefore targeting DNA GyrB domain may overcome this resistance issue, establishing it as an attractive target. This review is a compilation of current research efforts on energy supplying domain of Mycobacterium tuberculosis that could provide breakthrough in development of more potent Mtb DNA GyrB inhibitors.