Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice

Antimicrob Agents Chemother. 2012 Sep;56(9):4738-45. doi: 10.1128/AAC.00447-12. Epub 2012 Jun 25.


Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adhesins, Escherichia coli / genetics
  • Animals
  • Bacterial Adhesion / drug effects
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Catheter-Related Infections / drug therapy*
  • Catheter-Related Infections / microbiology
  • Cross Infection / drug therapy*
  • Cross Infection / microbiology
  • Drug Therapy, Combination
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • Female
  • Fimbriae Proteins / deficiency
  • Fimbriae Proteins / genetics
  • Gene Deletion
  • Mannosides / pharmacology*
  • Mannosides / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Molecular Weight
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacology*
  • Trimethoprim, Sulfamethoxazole Drug Combination / therapeutic use
  • Urinary Bladder / drug effects
  • Urinary Bladder / microbiology
  • Urinary Catheters / microbiology
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / microbiology
  • Uropathogenic Escherichia coli / drug effects*
  • Uropathogenic Escherichia coli / growth & development
  • Uropathogenic Escherichia coli / pathogenicity


  • Adhesins, Escherichia coli
  • Mannosides
  • fimH protein, E coli
  • Fimbriae Proteins
  • Trimethoprim, Sulfamethoxazole Drug Combination