title: In vivo and in vitro patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School-Twin Cities, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Oppegard
authors.forename: Bree L
authors.initials: BL
authors.lastname: Hamann
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Streck
authors.forename: Keith C
authors.initials: KC
authors.lastname: Ellis
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fiedler
authors.forename: Arkady B
authors.initials: AB
authors.lastname: Khodursky
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiasa
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology; D003470:Culture Media; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D013303:Streptomyces antibioticus / Q000254:growth & development / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors
chemical_list: D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D003374:Coumarins; D003470:Culture Media; D029968:Escherichia coli Proteins; D006027:Glycosides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D059005:Topoisomerase II Inhibitors; C083496:AcrB protein, E coli; C510997:angucyclinone; C416814:simocyclinone D8