Abstract：Since the invention of the first quinolone-class drug, nalidixic acid, in 1962, four generations and hundreds of new derivatives have been made and bacterial type IIA topoisomerases (DNA gyrase and topoisomerase IV) have been identified as the targets of such antibacterial agents. Previous studies have shown that bacterial DNA replication, which requires the cooperation of DNA gyrase and topoisomerase IV, is a vital process for bacterial growth and survival. The widespread clinical applications and huge success of type IIA topoisomerase-targeting agents in the past 50 years have also demonstrated the clinical relevance of this class of antimicrobials. However, misuse and over-use of the quinolone-based compounds have led to a steady increase in bacterial resistance. To preserve the usefulness of this proven target for treatment efficacy, development of novel, non-quinolone agents that can bypass existing quinolone resistance is urgently needed.