title: Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis.
abstract: BACKGROUND
  Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms.
  
  
  METHODS
  We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis.
  
  
  RESULTS
  The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 μM (0.12 μg/ml) for B. subtilis, 1.5 μM (0.64 μg/ml) for S. aureus, 2 μM (0.86 μg/ml) for B. cereus and 10 μg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier.
  
  
  CONCLUSIONS
  These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development.
  
  
  CONCLUSIONS
  We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, Umeå, Sweden. Electronic address: tomas.gustafsson@umu.se.
authors.forename: Tomas N
authors.initials: TN
authors.lastname: Gustafsson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Harer
authors.initials: H
authors.lastname: Osman
authors.affiliation: Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Jim
authors.initials: J
authors.lastname: Werngren
authors.affiliation: Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.affiliation: Department of Chemistry, BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Engman
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Biochemistry, Karolinska Institutet, Stockholm, Sweden. Electronic address: arne.holmgren@ki.se.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001407:Bacillus / Q000187:drug effects*; D001408:Bacillus anthracis / Q000201:enzymology*; D054833:Isoindoles; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D013880:Thioredoxin-Disulfide Reductase
keywords: Antibiotic resistance; Drug target; Mycobacterium tuberculosis; Redox biology; Staphylococcus aureus; Thioredoxin reductase