Microbial “irony”—bacteria provide keys to battling urinary tract infections
Researchers have identified two different molecules that can limit growth of microbes that cause urinary tract infections (UTIs), adding to approaches being pursued to develop new strategies for clinical treatment of UTIs. UTIs are very common and primarily affect women, who often go on to suffer long-lasting or repeated infections. The majority of UTIs are caused by bacteria. Although still treatable with available antibiotics, a steady and alarming increase in antibiotic-resistant bacteria has led researchers to seek out other ways to prevent or treat UTIs. Exploiting the knowledge that bacteria need host-supplied iron in order to survive—and that human hosts limit iron access during infection—is one very promising avenue of research.
UTIs are most commonly caused by uropathogenic Escherichia coli, or UPEC. Whereas E. coli normally live in the human intestinal tract and benefit health, some strains possess factors that help them, with varying degrees of success, to colonize the urinary tract and cause disease. For example, UPEC that possess a genetic element called the Yersinia high pathogenicity island (HPI) can make a special iron-scavenging molecule, called a siderophore, that helps them obtain iron even as the host tries to fight infection by limiting its availability. Scientists have now found evidence that the HPI also enables UPEC to produce a second molecule, called escherichelin, that inhibits a siderophore produced by a totally different species of bacteria that can also cause UTIs. This finding—together with some initial findings in humans—not only provides insight into how some UPEC may eliminate microbial competitors, but also suggests that E. coli strains that can colonize the urinary tract and produce escherichelin but not cause disease (asymptomatic strains) might be useful as “probiotics” to prevent opportunistic UTIs caused by other bacteria.
In a second study, a different team of researchers sought out molecules that could inhibit UPEC growth itself. One of the first antibiotics ever identified, penicillin, is a natural product of a certain mold, and kills susceptible bacteria by inhibiting a key step in how they create their unique cellular “wall.” Similarly, the research team looked to an extensive library of naturally produced molecules, rather than synthesized chemicals, to screen for any that could limit UPEC growth under low iron conditions similar to those found during UTI. They hoped to find molecules that didn’t bind up (chelate) iron and further reduce its availability to have this effect, but instead could target UPEC cellular processes active during “normal” infection. From their screening process, they isolated a novel molecule produced by a bacterial species called Streptomyces nicoyae (S. nicoyae), which they termed nicoyamycin A, or NicA. Testing revealed that purified NicA and two similar molecules subsequently isolated from S. nicoyae are potent inhibitors of UPEC growth in low iron conditions. However, despite efforts during the initial screens to exclude iron-chelating molecules, purified NicA (as well as the other two molecules) was subsequently found to be a potent iron chelator. Still, it is known that some antimicrobial molecules, such as the antibiotic tetracycline, have iron-chelating properties, even though that is not their primary mode of action. Thus, further studies of NicA and related molecules from S. nicoyae could reveal if this is the case, and, if so, the relative contributions of different molecular properties to their inhibition of UPEC growth. Encouragingly, a second set of molecules similar to NicA that were also tested inhibited UPEC growth but did not potently chelate iron, suggesting a greater likelihood that NicA and the other molecules act through another mechanism. In the meantime, the identification of multiple bacterial-produced molecules, such as escherichelin and NicA, that hamstring UTI-causing organisms under conditions of low iron is an encouraging step forward in finding new therapeutic strategies to combat UTIs.
Ohlemacher SI, Giblin DE, d'Avignon DA,…Henderson JP. Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030. doi: 10.1172/JCI92464, 2017.