title: Reutericyclin and related analogues kill stationary phase Clostridium difficile at achievable colonic concentrations.
abstract: OBJECTIVE
  The stationary phase of Clostridium difficile, which is associated with the symptoms of the diarrhoeal disease, is refractory to antibiotic killing. The aim of this study was to explore whether probiotic-derived reutericyclin and related synthetic analogues could kill stationary phase C. difficile at concentrations achievable in the gastrointestinal tract.
  
  
  METHODS
  The bactericidal activities of reutericyclin and lead compound derivatives were examined against logarithmic and stationary phase cultures of different C. difficile strains. The absorption of compounds across the intestinal epithelia was tested using the Caco-2 permeability model.
  
  
  RESULTS
  Unlike vancomycin and metronidazole, reutericyclins demonstrated concentration-dependent killing, being rapidly bactericidal against both logarithmic and stationary phase cells, at low concentrations (0.09-2 mg/L). The intestinal absorption of unmodified reutericyclin was poor and comparable to that of vancomycin. However, this property varied significantly for the synthetic reutericyclin analogues, ranging from well absorbed to non-absorbed. The non-absorbable compounds were highly effluxed, suggesting this parameter could be modulated to obtain agents with superior efficacy.
  
  
  CONCLUSIONS
  Reutericyclins showed excellent potency against the lethal non-growing stage of C. difficile at concentrations that may be attained in the gastrointestinal tract. Since these agents represent novel potential treatments for C. difficile infection, further development of this compound class is warranted.
authors.affiliation: Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Amy E
authors.initials: AE
authors.lastname: Heathcott
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018938:Caco-2 Cells; D016360:Clostridioides difficile / Q000187:drug effects*; D003106:Colon / Q000737:chemistry*; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects*; D013720:Tenuazonic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C416127:reutericyclin; D013720:Tenuazonic Acid