A new “super-antibiotic” has been developed to combat drug resistant bacteria, which is 25,000 times stronger than its predecessor, vancomycin 1.0. The new drug, vancomycin 3.0, uses a three-pronged method to combat resistant microbes. Vancomycin 1.0 has been in use since 1958 against infections such as methicillin-resistant Staphylococcus aureus. The original version of the drug is considered a “drug of last resort,” for when other antibiotics fail. It kills bacteria by preventing them from building cell walls, binding to protein fragments called peptides, targeting those that end with two copies of the amino acid D-alanine.

But now, bacteria have evolved resistance to the original drug, by replacing one of the D-alanine acids with D-lactic acid, interfering with vancomycin’s efforts to bind with its target. That trait has now spread, making drug-resistant versions of enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) increasingly common. Data from the US Centers for Disease Control and Prevention has shown that 23,000 Americans die each year from drug resistant infections in general.

To create the new drug researchers synthesized new versions of vancomycin that can bind to peptides ending in either D-alanine or D-lactic acid. They accomplished that goal in 2011, and since then, other researchers have found new ways for the drug to kill bacteria. Some research found new ways to stop the building of cell walls, while other research found ways to cause the outer cell membrane to leak, killing the cell.

The team, led by Dale Boger, a chemist with Scripps Research Institute in San Diego, has now put those three innovations together to create the new superdrug. This week they published their research in Proceedings of the National Academy of Sciences, saying the drug was 25,000 times stronger against VRE and VRSA. Their research also found that microbes were much slower to develop resistance to the new drug.

“Organisms just can’t simultaneously work to find a way around three independent mechanisms of action,” said Boger. “Even if they found a solution to one of those, the organisms would still be killed by the other two.”

The research shows the potential of designing the functions of antibiotics to address drug resistance. Most antibiotic compounds are found through trial and error.

Boger said, however, that the compound is not yet ready for human trials. His team will now look for ways to simplify and shorten the production process, which currently requires 30 chemical steps, so the drug can be produced more cheaply. Next, it will be tested on animals, and finally, humans.

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