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

Marcus J. Edwards, Ruth H. Flatman, Lesley A. Mitchenall, Clare E. M. Stevenson, Tung B. K. Le, Thomas A. Clarke, Adam R. McKay, Hans-Peter Fiedler, Mark J. Buttner, David M. Lawson, Anthony Maxwell

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)
4 Downloads (Pure)

Abstract

Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.
Original languageEnglish
Pages (from-to)1415-1418
Number of pages4
JournalScience
Volume326
Issue number5958
DOIs
Publication statusPublished - 4 Dec 2009

Cite this