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Metabolomics Study Uncovers Potential UTI Drug Targets

NEW YORK (GenomeWeb News) – Escherichia coli strains associated with recurrent urinary tract infections secrete higher than typical levels of two specific iron-scavenging molecules, according to a paper appearing online last night in PLoS Pathogens.

A team of researchers from Washington University School of Medicine in St. Louis, the University of Washington, and the University of Miami used quantitative metabolomics to evaluate the metabolites secreted by the E. coli strains isolated from more than a dozen women with recurrent UTIs. When they compared these to metabolites released by other gut microbes isolated from the same individuals, the team discovered that UTI-related strains were more apt to produce the iron-grabbing siderophores yersiniabactin and salmochelin.

Based on these results, researchers say, it may be possible to create therapeutics that preferentially target recurrent UTI-causing bacteria without wiping out beneficial or neutral bacteria.

"Our interest is in perhaps targeting the pathogenic bacteria more specifically," lead author Jeffrey Henderson, a physician and infectious disease researcher at Washington University School of Medicine, told GenomeWeb Daily News.

Roughly half of women will get a UTI at least once in their lives. The bacterial infections can affect the urethra, bladder, or kidneys — and about 90 percent of the time, E. coli is the culprit. But not all E. coli strains are pathogenic. Some actually seem to aid in host digestion and may interfere with bugs that would be pathogenic to the host.

One potential difference between "good" and "bad" E. coli: siderophores, a family of small molecules secreted by some microbes to scavenge and bind ferric iron before being taken back up by cells. Iron is a precious resource — and one that mammalian hosts generally guard carefully. Previous research suggests pathogenic bacteria may be more prone than other bugs to secreting siderophores, which can snatch iron from their hosts.

"Siderophores effectively compete with mammalian iron storage proteins and may be of particular importance in acquiring this critical nutrient during infection," the authors explained. "Additional horizontally-acquired genes facilitating siderophore biosynthesis may confer new or enhanced properties that may render a bacterium more virulent."

In an effort to find new ways to distinguish between nice or neutral E. coli strains and the nasty UTI-causing strains, the researchers used metabolomics to compare siderophores released by both UTI-related bacteria and normal flora.

"I think there are definitely some advantages to looking at metabolomics over genetics alone," Henderson said. "What we're looking at is the end products of many genes working together."

After initial studies to understand the expression of metabolites secreted by 18 previously isolated human uropathogenic strains grown under high- or low-iron conditions, the team turned their attention to patient samples.

Specifically, the researchers isolated bacterial strains from urine and rectal samples collected from 13 women, treated at the University of Washington, who had recurrent UTIs. Rectal samples were used as a proxy for normal gut flora, Henderson said.

The team grew urine and rectal bacteria under standard iron-limiting conditions, Henderson explained. They then applied stable isotope dilution mass spectrometry to glean both quantitative and qualitative information about the siderophores in each bacterial supernatant sample. By comparing metabolites secreted by "normal" bacteria and strains in the urine, the team got a window into products that might be linked to pathogenesis.

Their results suggest UTI-associated E. coli strains in urine produce higher than normal levels of two siderophores: yersiniabactin and salmochelin. On the other hand, the levels of two other siderophores — enterobactin and aerobactin — were similar to those secreted by normal gut bacteria in the control samples.

In general, this sort of siderophore-mediated iron acquisition by the pathogenic bacteria seems to help bugs grow more successfully in their hosts, Henderson explained. There's anecdotal evidence suggesting some individuals with recurrent UTIs have symptoms resembling iron-deficiency, he added, suggesting host efforts to keep iron from pathogenic bacteria may inadvertently hide it from host red blood cells too.

Based on their results, the researcher speculated that targeting yersiniabactin and salmochelin may yield new therapeutics that specifically knock out UTI-related bacteria while leaving other bugs relatively unscathed — an approach that would be less detrimental to the host's natural microbiome.

Most UTI treatments rely on very broad spectrum antibiotics, Henderson explained. These usually stop acute infections but don't seem to prevent future infections. Consequently, individuals often have recurrent infections involving the same strain that has infected them before.

"When we treat an infection with antibiotics, it's like dropping a bomb — nearly everything gets wiped out, regardless of whether it's helpful or harmful," Henderson said in a statement. "We'd like to find ways to target the bad bacteria and leave the good bacteria alone, and these siderophores are a great lead in that direction."

In the future, Henderson said he and his colleagues hope to help develop therapies based on their findings — either by targeting the siderophores themselves or by using a "Trojan horse" approach to deliver toxic compounds to pathogenic bacteria via the yersiniabactin and/or salmochelin receptors. They also plan to investigate whether siderophores have functional significance beyond iron acquisition, among other research questions.

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