New drug targets for urinary tract bacterial infections
Researchers have identified two molecules that enable Escherichia coli (E. coli), the bacterium that causes many urinary tract infections (UTIs), to survive and reproduce, thereby providing possible new targets for antibiotic therapy. These molecules, siderophores, are iron-chelating compounds secreted by microorganisms. The new 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.
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. 90% of all UTIs are caused by E. coli, which may come from the human gut, where several strains of the bacteria reside. 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, researchers 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 allowed them to look at the end products of many genes working together. Bacteria studied in the experiment came from patients with recurrent UTIs. The 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 is evidence that competition for 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 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. 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.
Quantitative Metabolomics Reveals an Epigenetic Blueprint for Iron Acquisition in Uropathogenic Escherichia coli. 2009 PLoS Pathog 5(2): e1000305
Bacterial pathogens are frequently distinguished by the presence of acquired genes associated with iron acquisition. The presence of specific siderophore receptor genes, however, does not reliably predict activity of the complex protein assemblies involved in synthesis and transport of these secondary metabolites. Here, we have developed a novel quantitative metabolomic approach based on stable isotope dilution to compare the complement of siderophores produced by Escherichia coli strains associated with intestinal colonization or urinary tract disease. Because uropathogenic E. coli are believed to reside in the gut microbiome prior to infection, we compared siderophore production between urinary and rectal isolates within individual patients with recurrent UTI. While all strains produced enterobactin, strong preferential expression of the siderophores yersiniabactin and salmochelin was observed among urinary strains. Conventional PCR genotyping of siderophore receptors was often insensitive to these differences. A linearized enterobactin siderophore was also identified as a product of strains with an active salmochelin gene cluster. These findings argue that qualitative and quantitative epi-genetic optimization occurs in the E. coli secondary metabolome among human uropathogens. Because the virulence-associated biosynthetic pathways are distinct from those associated with rectal colonization, these results suggest strategies for virulence-targeted therapies.
Related:
- Iron Uptake and Virulence
- Spread of Pathogenicity Islands in Escherichia coli
- The continuing evolution of E. coli O157:H7
Tags: Antibiotics, Bacteria, Biology, Health, Medicine, Microbiology, Science
