BACTERIAL TOPOISOMERASES, ANTI-TOPOISOMERASES, AND ANTI-TOPOISOMERASERESISTANCE

Topoisomerases are ubiquitous enzymes necessary for controlling the in terlinking and twisting of DNA molecules. Among the four topoisomerase s identified in eubacteria, two, DNA gyrase and topoisomerase IV, have been exploited by nature and the pharmaceutical industry as antibacte rial targets. Natural products that are inhibitors of one or both of t hese topoisomerases include the coumarin and cyclothialidine classes, which interfere with adenosine triphosphate hydrolysis, cinodine, flav ones, and terpenoid derivatives. The plasmid-encoded bacterial peptide s microcin B17 and CcdB also inhibit DNA gyrase. The quinolones, a syn thetic class of antibacterials that act on both DNA gyrase and topoiso merase IV, have had the broadest clinical applications, however, Quino lone congeners differ in their relative potencies for DNA gyrase and t opoisomerase IV. Studies of an expanding set of resistant mutant enzym es and the crystal structure of the homologous enzyme in yeast have co ntributed to our understanding of interactions of these drugs with top oisomerase-DNA complexes and the ways in which mutations effect resist ance.