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!
Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg
New potential cancer treatment using microwaves to target deep tumors
12.10.2016 | University of Texas at Arlington
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences