Nonfluoroquinolone-Based Inhibitors of Mycobacterial Type II Topoisomerase as Potential Therapeutic Agents for TB

Abstract Mycobacterium tuberculosis is a difficult pathogen to combat and the first-line drugs currently in use are 40–60 years old. The need for new TB drugs is urgent, in order to stem the tide of the disease globally and develop new, more effective treatments against drug-sensitive and -resistant strains. DNA gyrase, a class of enzymes known as topoisomerases, has attracted considerable attention as a potential antimycobacterial target. These enzymes are involved in the crucial processes of DNA replication, transcription, translation, and recombination in prokaryotic and eukaryotic cell regulation of DNA topology and its degree of supercoiling. DNA gyrase has no direct counterpart in eukaryotes. The indispensable nature of gyrase in the bacterial cells makes DNA gyrase an ideal drug target. Novobiocin and coumermycin inhibit DNA gyrase by binding to the ATP sites in GyrB, while the quinolone class inhibits these enzymes by binding to a site in GyrA near the intersection of the subunits and the associated DNA strand. This review broadly organizes small-molecule inhibitors of bacterial type II topoisomerase into GyrB inhibitors and nonfluoroquinolone-based GyrA inhibitors.