title: Diphosphonium ionic liquids as broad-spectrum antimicrobial agents.
abstract: OBJECTIVE
  One of the most disturbing trends in recent years is the growth of resistant strains of bacteria with the simultaneous dearth of new antimicrobial agents. Thus, new antimicrobial agents for the use on the ocular surface are needed.
  
  
  METHODS
  We synthesized a variety of ionic liquid compounds, which possess 2 positively charged phosphonium groups separated by 10 methylene units in a "bola"-type configuration. We tested these compounds for antimicrobial activity versus a variety of ocular pathogens, as well as their cytoxicity, in vitro in a corneal cell line and in vivo in mice.
  
  
  RESULTS
  The ionic liquid Di-Hex C10 demonstrated broad in vitro antimicrobial activity at low micromolar concentrations versus gram-negative and gram-positive organisms, including methicillin-resistant Staphylococcus aureus strains and ocular fungal pathogens. Treatment with Di-Hex C10 resulted in bacterial killing in as little as 15 minutes in vitro. Di-Hex C10 showed little cytotoxicity at 1 μM versus a corneal epithelial cell line or at 10 μM in a mouse corneal wound model. We also show that this bis-phosphonium ionic liquid structure is a key because a comparable monophosphonium ionic liquid is cytotoxic to both bacteria and corneal epithelial cells.
  
  
  CONCLUSIONS
  Here, we report the first use of dicationic bis-phosphonium ionic liquids as antimicrobial agents. Our data suggest that diphosphonium ionic liquids may represent a new class of broad-spectrum antimicrobial agents for the use on the ocular surface.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH, USA. georgeo@Dartmouth.edu
authors.forename: George A
authors.initials: GA
authors.lastname: O'Toole
authors.forename: Michel
authors.initials: M
authors.lastname: Wathier
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zegans
authors.forename: Robert M Q
authors.initials: RM
authors.lastname: Shanks
authors.forename: Regis
authors.initials: R
authors.lastname: Kowalski
authors.forename: Mark W
authors.initials: MW
authors.lastname: Grinstaff
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003320:Corneal Ulcer / Q000188:drug therapy* / Q000382:microbiology; D004195:Disease Models, Animal; D015818:Eye Infections, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000900:Anti-Bacterial Agents; D009943:Organophosphorus Compounds