One element links the disparate areas of research: 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 many other neurodegenerative disorders.
To probe amyloids' contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally 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 had also 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," says senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.
The findings were reported online in Nature Chemical Biology.
The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. 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 every year in the United States," says co-lead author Jerome S. Pinkner, laboratory manager for Hultgren. "We think it's likely that women who are 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 known as 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., a chemist 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. When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.
"Pili aren't made of amyloids, but they are essential to both biofilms and to the bacteria's ability to initiate an infection," Hultgren says.
Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.
Chapman cautions that it's too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.
"Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state," he says.
Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, published online.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Michael C. Purdy | EurekAlert!
Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory
‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong
Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...
An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications
Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...
Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.
The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
11.12.2017 | Physics and Astronomy
11.12.2017 | Earth Sciences
11.12.2017 | Information Technology