Scientists have designed small molecules that stop urinary tract infections (UTIs) from developing in mice by keeping bacteria from sticking to the wall of the bladder.
Since the new compounds do not destroy microbes or block their replication—as traditional antibiotics do—the researchers anticipate that bacteria responsible for most UTIs would have a harder time evolving resistance to them.
Traditional antibiotics have long been an effective treatment for UTIs. But microbes that have evolved clever defenses against these drugs are on the rise, creating a need for therapies that thwart bacteria in new ways, preferably without driving resistance.
“With increasing rates of antibiotic resistance, we are interested in finding new strategies to treat bacterial infections,” says James W. Janetka, an associate professor of biochemistry and molecular biophysics at Washington University School of Medicine in St. Louis. “The compounds we developed are promising because they prevent disease-causing bacteria from gaining a foothold in the bladder.
“They do not destroy microbes, so there should be no pressure favoring the survival of bacteria that are resistant to the compounds. We also have evidence that this may help preserve the beneficial bacterial communities already present in the microbiome.”
The newly developed compounds are called C-mannosides, and Janetka and his colleagues have shown that they can be delivered to mice by mouth in a liquid formulation to both treat existing UTIs and prevent such infections from developing.
The C-mannosides bind with high affinity to a protein called FimH, a virulence factor that resides on the surface of uropathogenic E. coli (UPEC), preventing bacteria from docking there and infecting those cells. With nothing anchoring them in place, these bacteria pass naturally from the mice when they urinate.
The C-mannosides improve on the design of the researchers’ previously reported molecules called O-mannosides, which block bacterial attachment in the same way but were shown to be less stable to metabolism when given to mice.
The news technology is the basis of the startup company Fimbrion Therapeutics.