Researchers have identified novel orally active compounds that appear to block uropathogenic E. coli bacteria from binding to bladder cells, thereby preventing new urinary tract infections (UTIs) and mitigating chronic infections in studies in mice. Infections of the urinary tract are common in women—about one-third of all women in the United States are diagnosed with a UTI by the time they reach 24 years of age—and many women experience repeated UTIs. Most UTIs are caused by a common type of E. coli bacterium. The outside surfaces of these bacteria contain hair-like projections that are tipped with a sugar-binding protein called FimH. FimH facilitates the binding of bacteria to human or mouse proteins containing mannose, a type of sugar, which are found on the surface of epithelial cells lining the bladder wall. Once attached to bladder cells, the bacteria become resistant to being flushed out by urine and can initiate infection. The bacteria form what is called a biofilm, a well-organized community that adheres to a surface. Bacteria can also invade bladder cells and establish an intracellular reservoir, thus producing a chronic infection. While antibiotic treatments are available, chronic and recurrent UTIs in women have become more challenging due to antibiotic resistance. To circumvent drug-resistant E. coli, there is an urgent need for new therapeutics to treat and prevent UTIs.
Because FimH is essential for successful infection by UTI-causing E. coli, scientists focused on finding a way to interfere with FimH binding to mannose as a possible new therapeutic strategy. First, they developed a panel of investigational compounds derived from mannose, called mannosides, and tested the ability of these mannose derivatives to block bacterial growth in a laboratory assay designed to mimic a biofilm. They then selected the most promising mannoside compound to evaluate its efficacy in treating and preventing UTI in a mouse model. Four mannoside compounds that were tested blocked biofilm growth when added at an initial stage of biofilm development or were capable of disrupting an established biofilm. The most potent mannoside was shown not only to reduce bacterial levels in bladders of mice with chronic UTIs, but also to do so more effectively than standard antibiotic treatment. Moreover, when administered prior to exposure to bacteria, the mannoside prevented new UTIs in mice. Like standard antibiotic treatment for UTIs, the mannoside was active when administered orally. Building on these results, the researchers were also able to generate additional, further optimized mannoside compounds as a starting point for new tests.
This promising finding of an alternative approach to UTI treatment emerges from a long-term research investment to understand the virulence and life cycle of uropathogenic E. coli, the primary culprit in UTIs in women. Future studies will continue to develop more potent mannosides and to assess these compounds for toxicity prior to their potential testing in humans.
Cusumano CK, Pinkner JS, Han Z, et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med 3: 109ra115, 2011.