Biofilm formation and migration on urethral catheters

Catheter-associated urinary tract infections (CAUTI) are the most frequent infections in hospitals and other health care facilitiesand put millions of patients worldwide at risk to develop more severe infections leading to sepsis. The high incidence of CAUTIs compared to uncomplicated urinary tract infections of the uncatheterized bladder is an indirect consequence of catheterization. Catheter insertion in the bladder (i) disrupts the constant flushing of the urethra providing easier access for bacteria to the bladder, (ii) circumvents complete bladder voiding leaving residual urine for rapid multiplication of intruding bacteria, and (iii) creates a surface subject to extensive biofilm formation that in turn provides a niche for bacterial growth with inherently increased antibiotic resistance. Achieving effective therapeutic strategies to control or prevent CAUTIs requires understanding the molecular mechanisms relevant in CAUTI pathogenicity. Bacterial migration and biofilm formation on urethral catheters are important virulence strategies of uropathogens causing CAUTI, yet, the molecular mechanisms underlying these processes are largely unknown. The proposed research will identify genetic factors crucial for bacterial migration and biofilm formation on urethral catheters by use of in vitro models that mimic the nutritional and physico-chemical conditions that prevail during CAUTI. We will evaluate those mutations affecting biofilm formation of uropathogens in laboratory biofilm model systems that also affect biofilm formation in a CAUTI model system. In parallel, we will use signature-tagged mutagenesis to identify novel virulence determinants of P. mirabilis crucial for colonization of urethral catheters in the presence and absence of a crystalline foundation layer. Finally, we will use two in vitro models of bacterial migration on urethral catheters to obtain insights into the molecular mechanisms that enable catheter migration of most prevalent uropathogens. These efforts are expected to broaden our understanding of CAUTI pathogencity which may ultimately provide novel molecular targets to prevent or combat CAUTIs.

Catheter-associated urinary tract infections (CAUTI) are the most frequent infections in hospitals and other health care facilities and put millions of patients worldwide at risk to develop more severe infections leading to sepsis. The high incidence of CAUTIs and their often chronic nature is an indirect consequence of insertion of catheter, since the catheter enables easier access of bacteria to the urinary bladder. Catheter insertion in the bladder creates a surface subject to extensive biofilm formation that in turn provides a niche for bacterial growth with inherently increased antibiotic resistance and recurrent infections. This collaborative project between the University of Applied Sciences and the University of Graz identified genetic factors crucial for bacterial migration and biofilm formation on urethral catheters. We identified those surface extensions called pili from Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae that are necessary for biofilm formation under conditions that mimic the nutritional and physico-chemical properties that prevail during CAUTI. Parallel assessment of catheter samples derived from infected patients support the conclusion that these factors are relevant for human infection. In addition we discovered a number of different factors that are necessary for efficient catheter and bladder colonization and persistence by the bacterial species Proteus mirabilis. We analyzed the stress response and physiological adaptations of the bacterial species required for infection.These results of this project provide molecular targets to prevent or combat CAUTIs. Collaborations were already established that pursue to test potential drugs that inhibit the discovered catheter adhesion factors and to develop anti-adhesive catheter coatings. In addition, interdisciplinary approaches aim to develop sensors for early detection of catheter-associated urinary tract infections.