Metabolomics reveals potential drug targets for bacteria causing urinary tract infections

Researchers at Washington University School of Medicine in St. Louis and the University of Washington have determined two molecules that enable Escherichia coli (E. coli), the bacteria that cause many urinary tract infections (UTIs), to survive and reproduce, thereby providing possible new targets for antibiotic therapy. These molecules, called siderophores, are discussed in a study published February 20th in the open-access journal PLoS Pathogens. The two siderophores, yersiniabactin and salmochelin, were shown to allow disease-producing bacteria strains to steal iron from their hosts, making it easier for these bacteria to survive and reproduce. Their identification also presents a potential way to selectively eradicate the pathogenic E.coli strains without adversely affecting those strains that normally populate the gut.

"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," says lead author Jeff Henderson, M.D., Ph.D. "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."

UTIs are among the most common bacterial infections worldwide. Half of all women will experience a UTI at some point in their lives, and in 20 to 40% of these patients, the infection recurs. Scientists believe 90% of all UTIs are caused by E. coli.

The E. coli that cause UTIs may come from the human gut, where several strains of the bacteria reside. Scientists think some of those strains help their human hosts by aiding digestion and blocking other infectious organisms. To study how friendly and infection-causing E. coli strains differ, Henderson and colleagues at the Center for Women's Infectious Disease Research at Washington University used a new approach called metabolomics. Instead of examining genes, metabolomics analyzes all the chemicals produced by a cell, which includes bacterial growth signals, toxins, and waste products.

"This allows us to look at the end products of many genes working together," says senior author Scott Hultgren, Ph.D. "We assess what all the various assembly lines are producing and which products disease-causing bacteria prefer to make, such as certain siderophores."

Bacteria studied in the experiment came from patients with recurrent UTIs treated at the University of Washington. Researchers cultured E. coli from both stool and urine samples and found that the strains from urine made more yersiniabactin and salmochelin.

Iron is an important nutrient typically kept under tight control by the host, and there's evidence that a back-and-forth contest centered on iron has been raging for millennia between disease-causing microbes and the hosts they exploit. There may, however, be multiple ways to take advantage of the infectious bacterial strains' reliance on siderophores. Researchers will try to block or disrupt the activity of the proteins that make siderophores, but they also may use what Henderson calls a "Trojan horse" strategy.

"To steal iron, siderophores have to be sent out from the cell, bind to the iron, and then be taken back into the cell," he explains. "If we can design an antibiotic that looks like a siderophore, we might be able to trick only disease-causing bacteria into taking up the drug while leaving other bacteria alone."

Source: Public Library of Science