Combinatorial Small-Molecule Therapy Prevents Uropathogenic Escherichia coli Catheter-Associated Urinary Tract Infections in Mice

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Escherichia coli</jats:named-content>(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.</jats:p>

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

“…In addition, mannoside compounds acted synergistically with TMP-SMZ to further reduce the level of CFU recovered from catheters and bladders 6 hours after infection (38). Unfortunately, these compounds, despite their efficacy in preclinical models, remain to be tested in clinical trials and are not currently available.…”

“…Treatment with mannoside compounds, which block the binding of UPEC to the bladder surface and prevent colonization, effectively limited implant and bladder colonization in a model of UPEC CAUTI when delivered intraperitoneally 30 minutes prior to catheterization (38). In addition, mannoside compounds acted synergistically with TMP-SMZ to further reduce the level of CFU recovered from catheters and bladders 6 hours after infection (38).…”

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…When tested in a mouse model, the mannosides were able to prevent UTI when given prophylactically or to treat an established chronic urinary tract infection (275). These molecules have been demonstrated to prevent and treat UPEC CAUTI in a mouse model (276). Furthermore, synergistic action was noted between mannosides and trimethoprim-sulfamethoxazole, suggesting the utility of adjuvant approaches in this setting (276).…”

“…These molecules have been demonstrated to prevent and treat UPEC CAUTI in a mouse model (276). Furthermore, synergistic action was noted between mannosides and trimethoprim-sulfamethoxazole, suggesting the utility of adjuvant approaches in this setting (276). Prophylactic administration of a mannoside molecule, compound ZFH-04269, was recently demonstrated to significantly reduce bacterial colonization of the bladder and to prevent acute UTI caused by an epidemic multidrug-resistant UPEC ST131 clone.…”

Genotypic detection of the virulence factors of uropathogenic Escherichia coli isolated from diarrheic and urinary tract infected patients in Khartoum State, Sudan

“…It is well documented that type 1 pili are important for the invasion and persistence of the UPEC in the urinary bladder after its colonization. Type 1 pili colonization is enhanced by adhesin FimH (Hannan et al, 2012) encoded by fimH gene which recognizes certain α1β3 integrins (Guiton et al, 2012;Eto et al, 2007). It was also confirmed that FimH is important in pathogenesis and that the pathogenicity of a UPEC strain depends greatly on the ability of FimH to switch between conformations and this is also dependent on the different alleles that can be expressed by this gene, affecting FimH conformation …”