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
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences