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 bi nd 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."