Urinary tract infections (UTIs) present a substantial health problem for women, particularly when infections are chronic, recurrent or recalcitrant because of pathogenic mechanisms or antibiotic resistance. In the US, about 15 million women suffer from UTIs each year; 20–40% of women experience recurring infections. Healthcare costs associated with UTIs exceed $2.5 billion per year in the US, according to one estimate.

Most UTIs (85% or more) are caused by uropathogenic strains of Escherichia coli. The bacteria enter the urinary tract and use a special fiber called a pilus to attach to the epithelial cells and to each other, forming intracellular bacterial communities. These attachments protect bacteria from host defenses and from antibiotics, contributing to recurrent infections and antibiotic resistance. UTIs are commonly treated with the antibiotic trimethoprim-sulfamethoxazole (TMP-SMZ), but drug-resistant uropathogens are increasing in prevalence and distribution, making UTI a growing public health concern. There is a pressing need for new, effective treatments that neither suffer from nor contribute to antibiotic resistance.

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Because pilus binding is essential for the colonization, invasion and resistance of uropathogenic E. coli, it represents a potential new target for antimicrobial drugs. Pilus binding is directed by mannose, a component of microbial cell walls. Recently, a group of researchers at Washington University School of Medicine (St. Louis, MO) led by Scott J. Hultgren and James W. Janetka investigated whether disrupting mannose-mediated activity could interfere with pilus binding and improve treatment of UTIs caused by uropathogenic E. coli. They developed a series of low-molecular-weight mannose derivatives called mannosides and evaluated their antimicrobial efficacy in vitro and their bioavailability in mice. The efficacy of the most promising of the mannosides, called compound 6, was then tested in a mouse model of chronic UTI. Within 6 hours of treatment, mice given compound 6 had significantly lower bacterial numbers in their bladders (Sci. Transl. Med. doi:10.1126/scitranslmed.3003021; published online 16 November 2011). Mice given TMP-SMZ also experienced a significant, but smaller, decrease in bacterial numbers.

Compound 6 also prevented mice from developing UTIs when administered prophylactically. “This drug can block the spread of the bacteria that cause urinary tract infections far better than any other previously reported compound,” said Hultgren in a press release. “If it has similar effects in humans, the potential applications would be very exciting.”

The researchers have continued to modify compound 6 to improve its pharmacokinetic profile, especially its oral bioavailability. Hultgren and Janetka hope to begin human toxicity tests of the mannosides during 2012, with clinical trials to follow.