DALLAS, Texas, USA — Aug. 21, 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.

Dr. Vanessa Sperandio, associate professor of
microbiology and biochemistry, led research that uncovered a potential
new way to stop the biochemical signals that cause bacteria in our
bodies to release toxins. The team's investigation could provide a
novel approach to combating illness.

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.

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