Recent advancements in the medicinal chemistry of bacterial type II topoisomerase inhibitors

Replication proteins are sought as a potential targets for antimicrobial agents. Despite their promising target characteristics, only topoisomerase II inhibitors targeting DNA gyrase and/or topoisomerase IV have reached clinical use. Topoisomerases are the enzymes that are essential for cellular functions and various biological activities. A wide range of natural and synthetic compounds have been identified as potential topoisomerase inhibitors but the resistance is most commonly found in these drugs. The emergence of FQ resistance has increased the need for the development of novel topoisomerase inhibitors with efficacy and high potency against FQ-resistant strains. Besides structural modifications of existing FQ scaffolds, novel non-quinolone topoisomerase II inhibitors, known as novel bacterial topoisomerase inhibitors, have been developed which showed remarkable inhibitory activity against DNA gyrase/topoisomerase IV or both with an improved spectrum of antibacterial potency including drug-resistant strains. This review aims to summarize various recent advancements in the medicinal chemistry of topoisomerase inhibitors with the following objectives: (1) To represent inclusive data on types of topoisomerases and various marketed topoisomerase inhibitors as drugs; (2) To discuss the recent advances in the medicinal chemistry of various topoisomerase inhibitors (DNA gyrase and topo IV) belonging to different structural classes as potential antibacterial agents; (3) To summarizes the structure activity relationship (SAR) including in silico and mechanistic studies to afford ideas and to provide focused direction for the development of new chemical entities which are effective against drug-resistant bacterial pathogens and biofilms.