Targeting novel sites in DNA gyrase for development of anti-microbials

Abstract

Abstract Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in the appearance of multiple drug resistance in bacterial pathogens and a decline in the discovery of novel antibiotics. DNA gyrase is an attractive target used for antibiotic discovery due to its vital role in bacterial DNA replication and segregation in addition to its absence in mammalian organisms. Despite the presence of successful antibiotics targeting this enzyme, there is a need to bypass the resistance against this validated drug target. Hence, drug development in DNA gyrase is a highly active research area. In addition to the conventional binding sites for the novobiocin and fluoroquinolone antibiotics, several novel sites are being exploited for drug discovery. The binding sites for novel bacterial type II topoisomerase inhibitor (NBTI), simocyclinone, YacG, Thiophene and CcdB are structurally and biochemically validated active sites, which inhibit the supercoiling activity of topoisomerases. The novel chemical moieties with varied scaffolds have been identified to target DNA gyrase. Amongst them, the NBTI constitutes the most advanced DNA gyrase inhibitor which are in phase III trial of drug development. The present review aims to classify the novel binding sites other than the conventional novobiocin and quinolone binding pocket to bypass the resistance due to mutations in the DNA gyrase enzyme. These sites can be exploited for the identification of new scaffolds for the development of novel antibacterial compounds.