Antibiotic Grooves

As widespread resistance to existing antibiotics looms, drug developers are on the hunt for new ways to kill bacteria. Researchers led by Anthony Maxwell of the John Innes Centre, in Norwich, England, have found a new strategy: previously unknown grooves in the bacterial protein DNA gyrase (Science 2009, 326, 1415). Gyrase catalyzes the supercoiling of microbial DNA and is not found in humans, making the protein a valuable drug target because potential side effects can be reduced. For example, ciprofloxacin, a drug that can kill the causative agent of anthrax, targets gyrase. The new binding pockets were discovered when Maxwell’s team solved the X-ray crystal structure of a gyrase bound to an antibiotic called simocycli­none, which is derived from soil bacteria. In particular, simocyclinone can simultaneously dip into the two gyrase grooves, blocking the gyrase’s ability to bind DNA. Although simocyclinone is not powerful enough to develop into a drug, knowing where it binds in gyrase should provide inspiration to scientists who would like to chemically tweak the antibiotic to boost its bactericidal effects, Maxwell says. The binding pockets could also be inspiration for the design of entirely new molecules that might inhibit gyrase.