Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Newly discovered cell mechanism uses amplified nitric oxide to fight C. diff

23.08.2011
Research involving Case Western Reserve featured in the Aug. 21 online issue of Nature Medicine

Groundbreaking research encompassing Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, has uncovered a natural defense mechanism that is capable of inactivating the toxin that spreads Clostridium difficile, or C. diff, an increasingly common bacterial infection in hospitals and long-term care settings. The research has immediate implications for developing a new form of treatment for antibiotic-resistant bacteria.

The newly discovered mechanism involves a nitric oxide (NO)-based molecule, S-nitrosoglutathione (GSNO), which binds to the toxins secreted by C. diff bacteria to deactivate them and prevent them from penetrating and damaging cells. The mechanism encompasses S-nitrosylation (SNO), a protein modification that attaches NO to cysteine residues in enzymes and other proteins.

"We've discovered a natural defense against C. diff that is based on nitric oxide, a ubiquitous molecule that is often produced by immune cells to kill pathogens," says Jonathan Stamler, MD, director of the Institute for Transformative Molecular Medicine and the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation at the Case Western Reserve University Cardiovascular Center and University Hospitals Harrington-McLaughlin Heart & Vascular Institute. "Understanding how this mechanism deactivates toxins provides a basis for developing new therapies that can target toxins directly and thereby keep bacterial infections, like C. diff, from spreading," he says.

Dr. Stamler discovered the molecule GSNO, as well as the nitrosylation mechanism for control of protein function, in his previous research. He is one of the senior investigators studying how the protein modification inhibits the virulence of C. diff toxins. The resulting research findings appear in the Aug. 21 online issue of Nature Medicine.

In addition to Dr. Stamler, investigators from the University of Texas in Galveston, the University of California, Tufts University and the Commonwealth Medical College collaborated on the research. The University of Texas researchers first determined that NO helped protect cells against C. diff and approached Dr. Stamler to determine if SNO was also involved.

C. diff is the most common cause of hospital-acquired infectious diarrhea and life-threatening inflammation of the colon. It originates when normal, competing bacteria in the gastrointestinal tract are wiped out by the use of antibiotics. This allows C. diff bacteria to grow out of control.

The C. diff bacteria secrete a toxin that cleaves or cuts itself to generate a fragment that can penetrate cells, damaging them and resulting in a hemorrhagic injury to the gastrointestinal tract. The toxin is activated when inositolhexakisphosphate (InsP6), a substance prevalent in leafy vegetables and the gastrointestinal tract, binds to it, enabling the toxin to change shape and cleave itself.

The research shows that upon activation, GSNO, a NO donor molecule, binds to the toxin and nitrosylates it. This can only occur when InsP6 binds to the toxin.

The change in shape that results when InsP6 binds to the toxin is what enables the GSNO to target and inactivate the toxin by directly binding to the active site. There, the GSNO can nitrosylate (SNO) the cysteine to inactivate the toxin. These findings are especially significant as they suggest that GSNO has evolved to recognize shape changes in the toxins it targets.

Prior to this, researchers knew GSNO could produce SNO in many classes of proteins but there was little to no precedent for it binding to toxins or explaining how this SNO modification protects against infectious agents, Dr. Stamler says.

"The new research suggests GSNO, and S-nitrosylation, more generally, may have a universal function in protecting cells against microbial proteins, many of which have a design that is conducive to being s-nitrosylated by GSNO," Dr. Stamler says. "In this regard, GSNO-like molecules may represent a new class of antibiotics that can be developed, exploiting the shape changes in numerous bacterial proteins."

In their work, researchers also noted that increased levels of GSNO in the gut of C. diff-infected animals and increased levels of SNO-toxin in stools of patients, directly correlated with deactivation of the toxin, further confirming that the natural mechanism works to reduce disease activity in people. This provides a basis for measuring how much nitric oxide, a key molecule in cell immune activity, has bound to toxins to make SNO and limit the spread of bacteria.

The current treatment of C. diff is difficult and the infection often recurs. Resistance to antibiotics is also a serious worry. The researchers are currently developing a new class of anti-toxin treatment based on these findings. One advantage of such antitoxins, says Dr. Stamler, is that resistance won't occur. The researchers hope that the new treatment can enter clinical trials very rapidly.

Kevin Mayhood | EurekAlert!
Further information:
http://www.case.edu

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>