DNA gyrase as a drug target.

Abstract

he search for compounds to combat disease is never-ending. On the one hand, it is always desirable to seek drugs with improved prop- erties and, on the other, there is always the problem of re- sistance developing to existing compounds. Combating disease with drugs requires the identi- fication of a target: a cellular component which, when acted upon by a drug, will lead to the death (or arrest in growth) of the cell. One group of enzymes that have proved to be effective targets for therapeutic agents are the DNA topoisomerases. These enzymes are responsible for catalysing topological changes in DNA. A typical reaction, common to all topoisomerases, is the relaxation of DNA; in other words, the removal of DNA supercoils 1,2. Topoiso- merases are present in all cells (prokaryote and eukary- ote) and, in many cases, have been shown to be essen- tial for viability. As they have important functions in DNA replication, eukaryotic topoisomerases are tar- gets for antitumour agents, exploiting the fact that cancer cells divide more rapidly than other cell types. Camptothecin and etoposide are examples of anti- tumour drugs targeted to eukaryotic topoisomerases 3,4. In the case of prokaryotes, DNA gyrase has been found to be an effective target for therapeutic agents. Although gyrase is evolutionarily related to other topo- DNA gyrase is a remarkable enzyme, catalysing the seemingly complex reaction of DNA supercoiling. As gyrase is essential in prokaryotes, it is a good target for antibacterial agents. These agents have diverse chemical structures and interact with gyrase in a variety of ways.