As an extension of the multi-functional antibiotic platform, nitroimidazole-bearing hybrid antibiotics were synthesized that have specific utility in the treatment of anaerobic infections of the gastrointestinal tract.  In these efforts, distinct series of rifamycin-nitroimidazoles, quinolone-nitroimidazoles and oxazolidinone-nitroimidazoles have been synthesized that incorporate the metronidazole pharmacophore.  Metronidazole is a pro-drug that is activated intracellularly in target pathogens propagated under anaerobic conditions through the action of one or more enzymes of the oxidoreductase class.  Metronidazole is used clinically in the treatment of a number of anaerobic infections and has most recently found prominence, along with vancomycin, as a first-line agent for the treatment of serious lower GI disease states associated with Clostridium difficile infections.  However, relatively high rates of relapse and treatment failure have been associated both with vancomycin and metronidazole therapy for C. difficile associated disease (CDAD). New therapies are needed for this potentially life-threatening condition.  The novel metronidazole-bearing hybrid antibiotics are designed to address the key liabilities that are thought to be associated with the relapse phenomenon and achieve both faster and more complete eradication of CDAD.

In the GI Diseases program, specific chemistry ensures that the metronidazole-bearing hybrid antibiotics are restricted to the GI tract and therein do not exhibit systemic exposure following oral dosing.  Optimization studies using in vitro assays, including the use of anaerobic bacteria that exhibit resistance to the parental antibiotic pharmacophores, have revealed that the metronidazole-bearing hybrid antibiotics exhibit apparent synergy that cannot be experimentally duplicated with cocktail combinations of the parent antibiotics.

 

Clostridium difficile Associated Diseases (CDAD)

  • Commensal Gram-positive anaerobe of the lower GI tract
  • Opportunistic pathogen in GI surgery patients and those on extended antibiotic therapy:
    • Toxins released trigger bowel inflammation and severe diarrhea
    • Life-threatening in elderly and immunocompromised patients
  • Occurs in 400,000 hospitalized patients per year in US:
    • Length of stay extended 3.6 days; ~$3,600 per patient
    • 2005 US hospital costs attributable to CDAD estimated at >$1B
  • Oral vancomycin and oral metronidazole are 1st-line agents
    • Each associated with 15-20% relapse rate
    • Vancomycin use has led to emergence of Vanco-R Enterococci (VRE)
    • Oral vancomycin (VancocinTM, Viropharma) ‘06 sales $170M; ’07 range $195-205M

 

Helicobacter pylori Associated Diseases

  • Gram-negative, spiral shaped, motile, microaerophilic bacterium
  • Colonizes the stomach and upper gastrointestinal tract in the mucinlayer
  • Estimated that half the world’s population are H. pylori carriers
  • Major cause of chronic gastritis and key factor in duodenal and gastric ulcers as well as gastric adenocarcinoma
  • H. pylori therapy involves 2 to 4 antibiotic combinations with either a proton pump inhibitor or bismuth salicylate; 2 to 4 weeks of therapy standard
  • Patient compliance, resistance/relapse are the major factors therapy failure