title: Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics.
abstract: BACKGROUND
  One way to address the growing problem of antimicrobial resistance is to revive old compounds that may have intrinsic lethal activity that is obscured by protective factors. Bicyclomycin is an old inhibitor of the Rho transcription terminator that by itself shows little rapid lethal activity. However, bicyclomycin participates in bacteriostatic synergy, which raises the possibility that conditions for lethal synergy may exist, perhaps through a suppression of protective factors.
  
  
  METHODS
  Bicyclomycin was combined with bacteriostatic inhibitors of gene expression, and bactericidal activity was measured with several cultured Gram-negative pathogens.
  
  
  RESULTS
  When used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of tetracycline, chloramphenicol or rifampicin led to rapid killing. Four other pathogen species, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica serotype Typhimurium and Shigella dysenteriae, also exhibited enhanced killing when bicyclomycin was combined with tetracycline or rifampicin. This lethal synergy was achieved at low concentrations (slightly above the MIC) for all agents tested in combinations. Follow-up work with E. coli indicated that lethal synergy arose from a blockage of transcription elongation. Moreover, lethal synergy was reduced when bicyclomycin was added 60 min before tetracycline, suggesting that bicyclomycin induces a protective factor.
  
  
  CONCLUSIONS
  The action of bicyclomycin illustrates the potential present in a largely abandoned antibacterial agent; it exhibits lethal synergy when coadministered with known, bacteriostatic inhibitors of gene expression. The identification of protective factors, which are currently uncharacterized, may reveal new ways to promote the lethal action of some old antibiotics.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Malik
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Li
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IA 52246, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kerns
authors.affiliation: Molecular and Cell Biology Department, Quantitative Biosciences Institute, University of California, Berkeley, CA 94720, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Berger
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren St., Newark, NJ, USA drlicaka@njms.rutgers.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Drlica
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004357:Drug Synergism; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C024504:bicozamycin
keywords: Acinetobacter baumannii; Escherichia coli; Klebsiella pneumoniae; back-tracking; gene expression inhibitors; transcription elongation complex
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