title: 3,4-dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I.
abstract: OBJECTIVE
  Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level.
  
  
  METHODS
  In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage-religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays.
  
  
  RESULTS
  DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage-religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I.
  
  
  CONCLUSIONS
  This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity.
authors.affiliation: Department of Chemistry,  University of Delhi, Delhi 110007,  India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Bansal
authors.forename: Devapriya
authors.initials: D
authors.lastname: Sinha
authors.forename: Manish
authors.initials: M
authors.lastname: Singh
authors.forename: Bokun
authors.initials: B
authors.lastname: Cheng
authors.forename: Yuk-Ching
authors.initials: YC
authors.lastname: Tse-Dinh
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D059004:Topoisomerase I Inhibitors; C009712:bis-benzimidazole; D004264:DNA Topoisomerases, Type I