Type II DNA Topoisomerases as Antibacterial Targets

DNA topoisomerases are a class of ubiquitous enzymes that maintain the topological structures of DNA in both prokaryotic and eukaryotic organisms. The enzymes catalyze DNA topoisomerization reactions through a sequential DNA breaking­ passing-resealing process, and are the targets of many important therapeutic agents for the treatment of cancer and bacterial infectious diseases. Quinolone antibacterial agents are known to target specifically to DNA gyrase, a bacterial type II DNA topoisomerase. The drugs have rapid bactericidal action that is believed to derive from their dual actions to inhibit the catalytic activity of the essential enzyme and, more importantly, to form a stable enzyme-DNA cleavable complex at a position ahead of the replication forks leading to a quick arrest of DNA replication, irreversible DNA damage and thus cell death. These inhibitors are small in size and simple in structure, but are extremely potent with the antibacterial potency reaching to a few nanograms per milliliter range. The high potency and specificity of these inhibitors is believed to be achieved by its unique capability to bind cooperatively to a partially denatured DNA pocket created by the target enzyme during the strand breaking­ passing steps of the catalysis. The inhibition model emphasizes the importance of the binding pocket conformation in determining the binding specificity and potency. This 'conformation-fitting model ' explains most structure-activity relationships of quinolones as well as observations in quinolone-resistance patterns. Recent publications imply that the target of quinolones may also be the bacterial topoisomerase IV, which is another essential type II enzyme discovered recently in E. coli and shown to be necessary for DNA segregation at the final stage of cell division. These two enzymes share high degree of sequence homology as well as quinolone sensitivity in vitro and in vivo. Results of genetic analysis of resistant mutants further support the notion that topoisomerase IV may be a primary target of quinolone action in Staphylococcus aureus.