While several antibiotics target a bacterium's cell wall, vancomycin binds to a specific component of this wall. Drug resistance results when the VRE actually alters these cell-wall components, interfering with the drug's ability to bind to the bacterium. According to the Centers for Disease Control, VRE were first reported in 1986, nearly 30 years after the introduction of the drug. The study, published in the Journal of the American Chemical Society, was conducted by Brendan M. Crowley, Ph.D. candidate at Scripps Research's Kellogg School of Science and Technology, and Professor Dale L. Boger of the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology.
"The continued rise of vancomycin-resistant infection poses a serious threat to hospital patients in the U.S. and around the world," Boger said. "These infections not only increase the length of hospital stays, but they raise patient mortality rates as well. Our successful synthesis of a novel vancomycin analogue with a molecular structure that restores much of the drug's binding ability could potentially lead to the development of a new generation of antibiotics that could prove far more effective against vancomycin-resistant infections than what is available today."
The most common strains of VRE-called VanA and VanB-are both capable of inhibiting the antibiotic's ability to bind to the bacteria to such a degree that the loss of antimicrobial activity is reduced nearly 1,000 fold, Boger said.
In the study, the scientists developed two different re-engineered antibiotics and compared them in an antimicrobial assay against VanA, a strain of the bacteria that is highly resistant to treatment by glycopeptide antibiotics, including vancomycin and teicoplanin (a somewhat newer drug similar to vancomycin). Both showed a significant increase in binding ability-roughly 40 times more potent than today's version of the drug. The actual re-engineering was extremely challenging, Boger said, requiring not only a detailed molecular level understanding of the origin of the vancomycin resistance but a total of 24 sequential chemical steps to prepare the new antibiotics; in this case, a single atom in vancomycin was altered to counter an analogous single atom change in the bacterial cell wall that accounts for the resistance.
The results, Boger added, suggest that no matter how the VRE altered the cell wall component, it was still sensitive to treatment by the re-engineered vancomycin analogues.
"The complex chemical synthesis of the glycopeptide antibiotics was developed with the specific idea that this breakthrough technology could be used to alter and enhance their therapeutic properties," Boger said. "We hope that our pioneering efforts will spur further research into the development of more potent antibiotics."
The study was supported by the National Institutes of Health and the Skaggs Institute for Chemical Biology as well as fellowship grants from Bristol-Myers Squibb and Fletcher Jones Foundation.
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
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