Nav: Home

Cystic fibrosis patients may breathe easier, thanks to bioengineered antimicrobials

September 24, 2007

CHAMPAIGN, Ill. -- By better understanding how antimicrobials bind and thereby get inactivated in the mucus of air passages, researchers at the University of Illinois may have found a way to help cystic fibrosis patients fight off deadly infections.

"While not a cure, this work has potential as a therapeutic strategy against bacterial infections in cystic fibrosis," said Gerard Wong a professor of materials science and engineering, of physics, and of bioengineering at the U. of I., and a corresponding author of a paper accepted for publication in the Proceedings of the National Academy of Sciences. The paper is to be posted this week on the journal's Web site.

Ordinarily, pulmonary passages are lined with a thin layer of mucus that traps bacteria and other pathogens. Moved along by the motions of countless cilia, the mucus also acts as a conveyor belt that disposes of the debris. In patients with cystic fibrosis, however, the mucus is more like molasses - thick and viscous. Because the cilia can no longer move the mucus, the layer becomes stuck, and the bacteria grow, multiply and colonize. Long-term bacterial infections are the primary cause of death in cystic fibrosis.

Using synchrotron X-ray scattering and molecular dynamics simulations, the researchers took a closer look at the mucous mess.

Debris in the infected mucus includes negatively charged, long-chained molecules such as mucin, DNA and actin (from dead white blood cells). It turns out most of the body's antimicrobials, such as lysozyme, are positively charged.

"We found that actin and lysozyme - two of the most common components in infected mucus - form ordered bundles of aligned molecules, which is something you don't expect in something as messy as mucus," said Wong, who also is a researcher at the university's Beckman Institute. "Held together tightly by the attraction of opposite charge, these bundles basically lock up the antimicrobials so that they are unable to kill bacteria."

The researchers then developed a computational model to mimic the biological system. "The model accurately predicted the structure of the actin-lysozyme bundles, and agreed quantitatively with the small-angle X-ray scattering experiments," said Erik Luijten, a professor of materials science and engineering, and of physics, as well as a researcher at the Beckman Institute and the other corresponding author of the PNAS paper.

The next step was to find a way to liberate the lysozyme, or prevent it from binding in the first place. Using their model, the researchers explored the consequences of varying the positive charge on the lysozyme.

"When we reduced the charge, we found a huge effect in our model," Luijten said. "The lysozyme would not bind to the actin. It floated around independently in the mucus."

Then, through genetic engineering, the researchers made lysozyme with roughly half the normal charge. Experiments confirmed the simulations; the reduced charge prevented lysozyme from sticking to actin, without significantly reducing the all-important antimicrobial activity.

Although much work remains, future cystic fibrosis patients might use an inhaler to deliver genetically modified charge-reduced antimicrobials to upper airways. There, these 'non-stick' antimicrobials would go to work killing bacteria, and mitigate against long-term infection.

The implications of this research extend into other areas as well. In water purification, for example, one of the steps involves putting positively charged molecules in the water to grab negatively charged pollutants. The resulting aggregates settle to the bottom of holding tanks and are removed from the water supply.

"A better understanding of how oppositely charged molecules bind in aqueous environments could lead to ways of removing emerging pathogens in water purification," Wong said.
-end-
Besides Wong and Luijten, co-authors of the paper are postdoctoral research associate and lead author Lori Sanders, lecturer Wujing Xian, graduate student Camilo Guáqueta, and undergraduate students Michael Strohman and Chuck Vrasich.

Funding was provided by the National Institutes of Health, the Cystic Fibrosis Foundation, the National Science Foundation and the U. of I. WaterCAMPWS Science and Technology Center. Portions of the work were carried out at the Stanford Synchrotron Radiation Laboratory and at the Advanced Photon Source.

University of Illinois at Urbana-Champaign

Related Cystic Fibrosis Articles:

Cystic fibrosis alters the structure of mucus in airways
Cystic fibrosis (CF) alters the structure of mucus produced in airway passages.
Cystic fibrosis study offers new understanding of silent changes in genes
Researchers studying the root cause of cystic fibrosis have made a major advance in our understanding of silent gene changes with implications for the complexity of cystic fibrosis.
New imaging technique shows effectiveness of cystic fibrosis drug
Cystic fibrosis currently has no cure, though a drug approved by the Food and Drug Administration treats the underlying cause of the disease.
New study resolves the structure of the human protein that causes cystic fibrosis
In order to better understand how genetic mutations give rise to cystic fibrosis, researchers need to map the protein responsible for the disorder.
New molecules identified that could help in the fight to prevent cystic fibrosis
New research has identified new molecules that could help in the fight to prevent diseases caused by faulty ion channels, such as cystic fibrosis.
Newborn screening for cystic fibrosis
A new study led by a team from the Research Institute of the McGill University Health Centre and Cystic Fibrosis Canada reinforces the benefits of newborn screening for cystic fibrosis (CF) patients.
Evolving insights into cystic fibrosis lung infections
Recent research progress into how bacteria adapt and evolve during chronic lung infections in cystic fibrosis patients could lead to better treatment strategies being developed, according to a new review by the University of Liverpool.
Key hurdle overcome in the development of a drug against cystic fibrosis
In people suffering from cystic fibrosis the CFTR protein is not located in the right place in mucus-producing cells: it remains inside the cell while it should be in the cell wall.
Researchers further illuminate pathway for treatment of cystic fibrosis
By studying alveolar macrophages, which provide our airways with a crucial defense against pathogens, UNC scientists are now able to more fully understand the larger picture of CF symptoms and continue progress towards targeted treatments, aside from addressing the mutated CFTR gene.
Gene therapy: A promising candidate for cystic fibrosis treatment
An improved gene therapy treatment can cure mice with cystic fibrosis (CF).

Related Cystic Fibrosis Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Don't Fear Math
Why do many of us hate, even fear math? Why are we convinced we're bad at it? This hour, TED speakers explore the myths we tell ourselves and how changing our approach can unlock the beauty of math. Guests include budgeting specialist Phylecia Jones, mathematician and educator Dan Finkel, math teacher Eddie Woo, educator Masha Gershman, and radio personality and eternal math nerd Adam Spencer.
Now Playing: Science for the People

#518 With Genetic Knowledge Comes the Need for Counselling
This week we delve into genetic testing - for yourself and your future children. We speak with Jane Tiller, lawyer and genetic counsellor, about genetic tests that are available to the public, and what to do with the results of these tests. And we talk with Noam Shomron, associate professor at the Sackler School of Medicine at Tel Aviv University, about technological advancements his lab has made in the genetic testing of fetuses.