"Tricked-out" Vancomycin Counters Bacterial Resistance
Scientists at the Scripps Research Institute have succeeded in increasing the killing power of vancomycin aglycon, an important antibiotic against which bacteria have been developing resistance. In a laboratory version of tricking or hot-rodding a vehicle, Brendan M. Crowley and Dale L. Boger modified the molecular structure of vancomycin and produced a new variant that is many times more effective against enterococcal bacteria.
Though this was a research project, their pioneering work proves that such modifications can be made -- and may be much less expensive than the years-long effort to find, purify and test replacement antibiotics.
Some technical details:
The scientists replaced a single atom from the molecular structure of vancomycin aglycon, a glycopeptide antibiotic that attacks the bacteria by inhibiting cell wall synthesis, significantly increasing the drug's spectrum of activity. In recent years, a number of the most common strains of enterococci have become resistant to vancomycin and use of the antibiotic has been under scrutiny. This re-engineering effort could help make the drug more effective in treating infections produced by vancomycin resistance enterococci (VRE), a serious and growing problem in the nation's hospitals.
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 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."