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Antimicrobial Agents and Chemotherapy, May 2009, p. 2110-2119, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01440-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vivo and In Vitro Patterns of the Activity of Simocyclinone D8, an Angucyclinone Antibiotic from Streptomyces antibioticus ^,

Lisa M. Oppegard,¹ Bree L. Hamann,² Kathryn R. Streck,¹ Keith C. Ellis,^3,4 Hans-Peter Fiedler,⁵ Arkady B. Khodursky,² and Hiroshi Hiasa^1*

Department of Pharmacology, University of Minnesota Medical School—Twin Cities, Minneapolis, Minnesota 55455,¹ Department of Biochemistry, Molecular Biology, and Biophysics and Biotechnology Institute, University of Minnesota, St. Paul, Minnesota 55108,² Department of Medicinal Chemistry and Institute for Therapeutic Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55414,³ Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298,⁴ Mikrobiologisches Institut, Universität Tübingen, Auf der Morgenstelle 28, D-72076 Tübingen, Germany⁵

Received 28 October 2008/ Returned for modification 8 December 2008/ Accepted 1 March 2009

Simocyclinone D8 (SD8) exhibits antibiotic activity against gram-positive bacteria but not against gram-negative bacteria. The molecular basis of the cytotoxicity of SD8 is not fully understood, although SD8 has been shown to inhibit the supercoiling activity of Escherichia coli gyrase. To understand the mechanism of SD8, we have employed biochemical assays to directly measure the sensitivities of E. coli and Staphylococcus aureus type II topoisomerases to SD8 and microarray analysis to monitor the cellular responses to SD8 treatment. SD8 is a potent inhibitor of either E. coli or S. aureus gyrase. In contrast, SD8 exhibits only a moderate inhibitory effect on S. aureus topoisomerase IV, and E. coli topoisomerase IV is virtually insensitive to SD8. The antimicrobial effect of SD8 against E. coli has become evident in the absence of the AcrB multidrug efflux pump. As expected, SD8 treatment exhibits the signature responses to the loss of supercoiling activity in E. coli: upregulation of gyrase genes and downregulation of the topoisomerase I gene. Unlike quinolone treatment, however, SD8 treatment does not induce the SOS response. These results suggest that DNA gyrase is the target of SD8 in both gram-positive and gram-negative bacteria and that the lack of the antibacterial effect against gram-negative bacteria is due, in part, to the activity of the AcrB efflux pump.

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* Corresponding author. Mailing address: Department of Pharmacology, University of Minnesota Medical School—Twin Cities, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455. Phone: (612) 626-3101. Fax: (612) 625-8408. E-mail: hiasa001{at}umn.edu

Published ahead of print on 9 March 2009.

Supplemental material for this article may be found at http://aac.asm.org/.

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Antimicrobial Agents and Chemotherapy, May 2009, p. 2110-2119, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01440-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.