Recent Developments in Inhibitors of Bacterial Type IIA Topoisomerases

Type II topoisomerases are a family of molecular machines, present in all cells, which choreograph a complex multistep catalytic cycle to transform DNA topology. Double‐stranded DNA cleavage, strand passage, and religation are linked to ATP hydrolysis, to supercoil, relax, decatenate, or unknot DNA. The DNA cleavage‐religation and ATPase domains present multiple sites for drug intervention, and are the targets of many classes of antibacterial and anticancer investigational and marketed drugs. The great variety of known inhibitors and their diverse mechanisms of action illustrate the molecular vulnerability of bacteria at these targets. However, it also highlights the challenge for drug developers, given that fluoroquinolones are still the only marketed antibacterial agents targeting type II topoisomerases. The structural basis of action of inhibitors acting at the DNA cleavage‐religation site, including fluoroquinolones and a novel class of antibacterial novel bacterial type II topoisomerase inhibitors (NBTIs), was only recently elucidated. This crystallographic platform, coming more than 40 years after the discovery of the quinolone antibacterials, provides new opportunities to explore the structural basis of action of other inhibitors, and to guide drug design and optimization to exploit this clinically validated target class.