DNA topoisomerases are ubiquitous
enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of
genomic stability. They have proved to be valuable targets for
therapy, in part because some anti-topoisomerase agents act as
poisons.
Bacterial DNA gyrase and
topoisomerase IV (type IIA topoisomerases) are targets of
fluoroquinolones while human
topoisomerase I (a type IB topoisomerase) and
topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent
phosphotyrosine DNA cleavage intermediate trapped by
drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial
topoisomerase I and cleaved
DNA can lead to bacterial cell death, supporting bacterial
topoisomerase I as a promising target for the development of novel
antibiotics. For current antibacterial
therapy, the prevalence of
fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by
fluoroquinolone resistant mutations on the gyrase or
topoisomerase IV genes. For anti-viral
therapy, poxviruses encode their own type IB topoisomerases; these
enzymes differ in
drug sensitivity from human
topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus
topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of
DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for
drug discovery in the treatment of
infectious diseases.