Research into Alzheimer’s disease seems an unlikely approach to yield a better way to fight urinary tract infections (UTIs), but that’s what scientists at the School of Medicine and elsewhere recently reported.
Hultgren
Linking the disparate areas of research are amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks. Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders.
To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes also had unexpectedly made them more effective UTI treatments.
“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” said senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology.
The findings were reported online in Nature Chemical Biology.
The National Institutes of Health has estimated that more than 80 percent of microbial infections are caused by bacteria growing in a biofilm. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.
“UTIs occur mainly in women and cause around $1.6 billion in medical expenses annually in the United States,” said co-lead author Jerome S. Pinkner, research lab manager in Hultgren’s lab. “We think it’s likely that women troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment.”
Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers called curli that are extruded by the bacteria to strengthen the structures of biofilms.
To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., professor of chemistry at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks. Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.
The alterations worked. In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease. In a mouse model of UTIs, researchers found that the altered compounds were better at reducing the virulence of infections.