A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase

Abstract

Targeting DNA Gyrase DNA gyrase, an enzyme that unwinds double-stranded DNA, is essential in bacteria, but missing in humans, and is thus an important antibiotic target. DNA gyrase is inhibited by the well-known fluoroquinolines and aminocoumarins antibiotics, as well as by symocyclinones—bifunctional antibiotics comprising an aminocoumarin and a polyketide group. Surprisingly, symocyclinones, unlike aminocoumarin inhibitors, do not inhibit DNA gyrase GTPase activity, but instead inhibit binding to DNA. Now Edwards et al. (p. 1415 ) use biochemical and structural studies to show that the two functional groups of the antibiotic bind in separate pockets on the gyrase. Each group is a relatively weak inhibitor that together potently inhibit DNA binding.