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Antimicrobial Agents and Chemotherapy, March 2005, p. 1093-1100, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1093-1100.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Simocyclinone D8, an Inhibitor of DNA Gyrase with a Novel Mode of Action

Ruth H. Flatman,1 Alison J. Howells,1 Lutz Heide,2 Hans-Peter Fiedler,3 and Anthony Maxwell1*

Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich, United Kingdom,1 Pharmazeutische Biologie, Pharmazeutisches Institut,2 Mikrobiologisches Institut, Tübingen, Germany3

Received 7 September 2004/ Returned for modification 23 October 2004/ Accepted 11 November 2004

We have characterized the interaction of a new class of antibiotics, simocyclinones, with bacterial DNA gyrase. Even though their structures include an aminocoumarin moiety, a key feature of novobiocin, coumermycin A1, and clorobiocin, which also target gyrase, simocyclinones behave strikingly differently from these compounds. Simocyclinone D8 is a potent inhibitor of gyrase supercoiling, with a 50% inhibitory concentration lower than that of novobiocin. However, it does not competitively inhibit the DNA-independent ATPase reaction of GyrB, which is characteristic of other aminocoumarins. Simocyclinone D8 also inhibits DNA relaxation by gyrase but does not stimulate cleavage complex formation, unlike quinolones, the other major class of gyrase inhibitors; instead, it abrogates both Ca2+- and quinolone-induced cleavage complex formation. Binding studies suggest that simocyclinone D8 interacts with the N-terminal domain of GyrA. Taken together, our results demonstrate that simocyclinones inhibit an early step of the gyrase catalytic cycle by preventing binding of the enzyme to DNA. This is a novel mechanism for a gyrase inhibitor and presents new possibilities for antibacterial drug development.

* Corresponding author. Mailing address: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, United Kingdom. Phone: 01603 450771. Fax: 01603 450018. E-mail: tony.maxwell{at}bbsrc.ac.uk.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1093-1100, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1093-1100.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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