Menachem Shoham, PhD, associate professor of biochemistry at Case Western Reserve University School of Medicine, has discovered novel antivirulence drugs that, without killing the bacteria, render Methicillin Resistant Staphylococcus Aureus (MRSA) and Streptococcus pyogenes, commonly referred to as strep, harmless by preventing the production of toxins that cause disease. The promising discovery was presented this week at the Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.
MRSA infections are a growing public health concern, causing 20,000 to 40,000 deaths per year in the United States alone. It is the most prevalent bacterial pathogen in hospital settings and in the community at large, with about one million documented infections per year nationally, costing an estimated $8 billion annually to treat.
The problem has become increasingly severe as the bacteria have developed a resistance to antibiotics. As result, health care providers are running out of options to treat patients suffering from antibiotic-resistant infections, like MRSA and strep, creating a dire need for alternative treatments and approaches.
"Staph bacteria are ubiquitous and normally do not cause infections, however, occasionally these bacteria become harmful due to their secretion of toxins," says Dr. Shoham. "We have discovered potential antivirulence drugs that block the production of toxins, thus rendering the bacteria harmless. Contrary to antibiotics, these new antivirulence drugs do not kill the bacteria. Since the survival of the bacteria is not threatened by this approach, the development of resistance, like that to antibiotics, is not anticipated to be a serious problem."
Dr. Shoham identified a bacterial protein, known as AgrA, as the key molecule responsible for turning on the release of toxins. AgrA, however, needs to be activated to induce toxin production. His goal was to block the activation of AgrA with a drug, thus preventing the cascade of toxin release into the blood that can lead to serious infections throughout the body.
The screening for AgrA inhibitors was initially carried out in a computer by docking libraries of many thousands of "drug-like" compounds and finding out which compounds would fit best into the activation site on AgrA. Subsequently, about 100 of the best scoring compounds were tested in the laboratory for inhibition of the production of a toxin that ruptures red blood cells. Seven of these compounds were found to be active. Testing compounds bearing chemical similarity to the original compounds lead to the discovery of additional and more potent so-called "lead" compounds.
Optimization of the initial "lead" compounds was performed by chemical synthesis of 250 new compounds bearing small but important chemical modifications on one of the initial leads. More than a dozen active compounds have been discovered by this method. The best drug candidate reduces red blood cell rupture by 95 percent without affecting bacterial growth.
Beginning this fall, Dr. Shoham and colleagues will begin testing the drug candidate in animal models.
"It is possible to inhibit virulence of MRSA without killing the bacteria," continues Dr. Shoham. "Such antivirulence drugs may be used for prophylaxis or therapy by themselves or in combination with an antibiotic. Antivirulence therapy may resensitize bacteria to antibiotics that have become ineffective by themselves."
This research was carried out in the laboratory of Dr. Menachem Shoham; funding was provided by grants from the Steris Corp., based in Mentor, Ohio, and the American Heart Association.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes -- research and scholarship, clinical mastery, leadership, and civic professionalism -- to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report, "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is affiliated additionally with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu.
Jessica Studeny | EurekAlert!
Purdue cancer identity technology makes it easier to find a tumor's 'address'
16.11.2018 | Purdue University
Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University
Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.
Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...
Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.
Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...
Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.
In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...
On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.
When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure
Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...
09.11.2018 | Event News
06.11.2018 | Event News
23.10.2018 | Event News
16.11.2018 | Health and Medicine
16.11.2018 | Life Sciences
16.11.2018 | Life Sciences