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Uncovering Drug Targets for Urinary Tract Infections

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The Escherichia coli behind recurrent urinary tract infections produce higher levels of iron-scavenging siderophores than non-disease-causing E. coli. Using a metabolomic approach, Jeffrey Henderson and his colleagues at Washington University School of Medicine in St. Louis found that disease-causing E. coli generate more salmochelin and yersiniabactin, presenting possible new avenues to treat recurrent UTIs.

"The approach was to actually look at these products themselves and do it in a quantitative manner so we know that we can see if strains produced more of each kind than a comparator," Henderson says.

Henderson and his colleagues collected E. coli isolates from urine from young women with recurrent urinary tract infections and compared them to the E. coli strains from rectal samples from the same women, taken at a different time, to compare the "bad" to the "good" E. coli. They grew the bacteria in iron-limiting conditions to determine which siderophores the bacteria expressed, as siderophores had been implicated in UTIs from previous genetic studies. "There was some idea iron acquisition was important in UTI, but we wanted to know something that's downstream from the actions of many genes," Henderson says. "We wanted to know what siderophores or secondary metabolites were preferentially produced by disease-causing E. coli, specifically those causing urinary tract infection."

By competing the strains from each individual patient against each other and looking at their metabolic profiles, Henderson was able to ask what made a disease-causing strain different from the others. The disease-causing strains produced more of two kinds of siderophores, salmochelin and yersiniabactin. "Even if the non-disease causing bacteria produced both or either of the siderophores, the disease-causing strains produced more," Henderson says.

They couldn't have gotten that bit of information, he adds, by using a genetic approach alone. "Both would show as genotype-positive," he says. Their metabolomic approach also directly connects the metabolic activity to disease.

The siderophores also present numerous potential targets for drug therapy. Not only could siderophore biosynthesis be targeted, so could the receptors that take the ironbound siderophores back up into the bacteria. Another possible approach is to turn an antibiotic into a "smart bomb." "You take an existing antibiotic and you chemically put something on that antibiotic that makes it look more like a siderophore," Henderson says. That way, the disease-causing bacteria are tricked into specifically taking up antibiotics and internalizing them.

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