Researchers Identify Key Structure of Bacteria that Could Lead to Future Treatments for Healthcare-Associated Infections

New Finding Identifies New Cell Binding Component on Clostridium Difficile Bacteria that Could Lead to New Structure-Based Drug Design for Life-Threatening Infections.

Researchers from the University of Maryland School of Medicine and their colleagues have identified the structure of the most lethal toxin produced by certain strains of Clostridium difficile bacteria, a potentially deadly infection associated with the use of antibiotics. The finding, published last week in the Proceedings of the National Academy of Sciences journal, used cryo electron microscopy, X-ray crystallography and other biophysical methods to identify the microscopic structures of the bacteria. The researchers mapped out the delivery and binding components of the toxin, which could pave the way for new drugs to neutralize it.

“We identified two structures that help explain the molecular underpinnings of C. difficile toxicity,” said study co-author David Weber, PhD, a Professor of Biochemistry and Molecular Biology and Director of the Center for Biomolecular Therapeutics at UMSOM. “These structures will be important for targeting this human pathogen using structure-based therapeutic design methods.”

Certain C. difficile infections are notoriously difficult to treat and often arise from antibiotic therapy given to fight other infections, which wipes out the beneficial bacteria that normally keep C. difficile bacteria in check. More than 500,000 cases occur annually in the United States, according to the Centers for Disease Control and Prevention, resulting in an estimated 15,000 deaths, usually from strains that are resistant to antibiotic treatment.

There is currently no drug approved by the Food and Drug Administration that targets the C. difficile toxin (CDT) or “binary toxin”.

The work was done in conjunction with researchers at the City University of New York, City College of New York, the National Institute of Standards and Merck & Co.

With the mapping of the structures of one of the binary toxins, called CDTb, the researchers next aim to answer important new questions regarding the molecular mechanism of the C. difficile toxin, which can also benefit drug discovery. For example, they will investigate how the active binary toxin complex assembles and dissociates, how it binds to a healthy cell in a patient’s gastrointestinal tract and how it enters the cell.

“This finding highlights the important mission of the Center for Biomolecular Therapeutics to facilitate the development of new treatments for potentially lethal infections,” said UMSOM Dean E. Albert Reece, MD, PhD, MBA, University Executive Vice President for Medical Affairs and the John Z. and Akiko K. Bowers Distinguished Professor. “The utilization of innovative biophysical imaging techniques in this study adds to the body of knowledge concerning this potentially deadly bacteria and will hopefully help pave the way for future treatments.”

This research was funded by the National Institutes of Health, National Science Foundation Division of Chemistry, and the U.S. Department of Health and Human Services.

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 45 academic departments, centers, institutes, and programs; and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.  With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has more than $540 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 student trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of nearly $6 billion and an economic impact more than $15 billion on the state and local community. The School of Medicine faculty, which ranks as the 8th highest among public medical schools in research productivity, is an innovator in translational medicine, with 600 active patents and 24 start-up companies. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu