Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Uncover Molecule Keeps Pathogens Like Salmonella in Check

22.08.2008
Scientists at UT Southwestern Medical Center have found a potential new way to stop the bacteria that cause gastroenteritis, tularemia and severe diarrhea from making people sick.

The researchers found that the molecule LED209 interferes with the biochemical signals that cause bacteria in our bodies to release toxins.

“What we have here is a completely novel approach to combating illness,” said Dr. Vanessa Sperandio, associate professor of microbiology and biochemistry at UT Southwestern and senior author of a study available online today and in a future issue of Science.

Though many antimicrobial drugs are already available, new ones are needed to combat the increasing microbial resistance to antibiotics. In addition, treating some bacterial infections with conventional antibiotics can cause the release of more toxins and may worsen disease outcome.

Scientists have known for decades that millions of potentially harmful bacteria exist in the human body, awaiting a signal that it’s time to release their toxins. Without those signals, the bacteria pass through the digestive tract without infecting cells. What hasn’t been identified is how to prevent the release of those toxins, a process that involves activating virulence genes in the bacteria.

In the new study, UT Southwestern researchers describe how LED209 blocks the bacterial receptor for these signals. In 2006, the UT Southwestern researchers were the first to identify the receptor QseC sensor kinase, which is found in the membrane of a diarrhea-causing strain of Escherichia coli. This receptor receives signals from human flora and hormones in the intestine that cause the bacteria to initiate infection.

In studies in vitro, Dr. Sperandio and her colleagues found that LED209 blocked the QseC sensors in E coli, Salmonella and Francisella tularensis bacteria, preventing them from expressing virulence traits. Using mice models of infection, the researchers also showed that LED209 blocks pathogenesis of Salmonella and F tularensis, preventing them from causing disease in these animals.

Though the researchers limited the study to three pathogens, they believe drugs that target QseC could have a broader spectrum because the sensor exists in at least 25 important animal and plant pathogens including Erwinia, which causes plant rot; Legionella pneumophila, which causes Legionnaires’ disease; and Haemophilus influenzae, which causes lung infections.

Unlike conventional antibiotics, which work by killing bacteria, LED209 allows the pathogen to grow but not become virulent and make the host sick. Dr. Sperandio said killing the bacteria or inhibiting their growth just “angers” some bacteria and causes them to release toxins.

“The sensors in bacteria are waiting for the right signal to initiate the expression of virulent genes,” she said. “Using LED209, we blocked those sensing mechanisms and basically tricked the bacteria to not recognize that they were within the host. When we did that, the bacterial pathogens could not effectively cause disease in the treated animals.”

Allowing the pathogen to survive also makes it less likely to develop resistance to medical treatments.

“What makes this current study unique is that we showed the drug working in three different pathogens,” Dr. Sperandio said. “Prior studies generally focused on one.”

In early 2008, UT Southwestern received a five-year, $6.5 million grant from the National Institute of Allergy and Infectious Diseases to develop a new antimicrobial compound to target bacterial pathogens such as Salmonella, E coli and F tularensis. Dr. Sperandio is the principal investigator.

“Only a few new antibiotics have reached the market in recent years,” Dr. Sperandio said. “Because LED209 has never been used as an antibiotic, it’s a completely different type of drug. In addition, its target, QseC, is also different from the current antimicrobial drug targets. This study demonstrates that LED209 has promise in fighting at least three pathogens and likely many more.”

Identifying LED209 was accomplished by using a high throughput screen of 150,000 compounds in UT Southwestern’s Small Molecular Library. The screening process was set up to find molecules that wouldn’t activate the virulence genes in a strain of E coli known as enterohemorrhagic E coli 0157:H7, or EHEC. Additional rounds of screening resulted in a pool of 75 potential inhibitors, from which LED209 was selected partly because of its potency.

The team’s next step is to understand further LED209’s structure and how it functions. The researchers plan to modify the drug to develop customized formulations.

“What we have right now works really well for systemic infections and it’s very potent, but we also need non-absorbable molecules to treat noninvasive pathogens such as EHEC, which stays in the intestine,” Dr. Sperandio said.

Other UT Southwestern researchers involved in this research were Dr. Noelle Williams, assistant professor of biochemistry; Dr. Ron Taussig, associate professor of pharmacology; Dr. Michael Roth, professor of biochemistry; Dr. John R. Falck, professor of biochemistry and pharmacology; Drs. Cristiano Moreira and Jason Huntley, both postdoctoral researchers in microbiology; Dr. Run Li, postdoctoral research in biochemistry; Dr. Shuguang Wei, senior research scientist in biochemistry; Maggy Fina, senior research associate in pharmacology; and student research assistants Nicola Reading and David Hughes. Dr. David Rasko, former assistant professor of microbiology at UT Southwestern, was the lead author. Drs. Matthew Waldor and Jennifer Ritchie from Brigham and Women’s Hospital also participated.

The work was funded by the National Institutes of Health, the Ellison Medical Foundation, Burroughs Wellcome Fund, the Welch Foundation and UT Southwestern’s High Impact/High Risk Research Program. UT Southwestern has filed a U.S. patent application on this technology.

Kristen Holland Shear | Newswise Science News
Further information:
http://www.utsouthwestern.edu
http://www.utsouthwestern.edu/findfac/professional/0,2356,50556,00.html

Further reports about: Biochemistry Coli LED209 Pathogen QseC Salmonelle Sperandio bacterial

More articles from Life Sciences:

nachricht New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa

nachricht New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

Im Focus: Researchers 3D print metamaterials with novel optical properties

Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna

A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

18.04.2019 | Physics and Astronomy

New eDNA technology used to quickly assess coral reefs

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>