Sabotaging Bacterial Resistance

The rise of bacteria resistant to antibiotics has left researchers scrambling to develop more powerful drugs. But in the latest issue of the Proceedings of the National Academy of Sciences, researchers report their first success with an unconventional strategy: tricking the upstart bacteria into scrapping their defenses.

Getting the bacteria to give up their resistance required some genetic sleight of hand. Sidney Altman and his colleagues at Yale University used one of the bacteria's own enzymes, called RNase P, to disable RNA made from genes that had been linked to drug resistance. They designed a short piece of DNA, called an external guide sequence (EGS), whose RNA binds to the RNA template used to make proteins that confer drug resistance. The EGS was slipped into the cell in a circle of DNA called a plasmid. Combined, these two pieces of RNA look like RNase P's normal target, so the enzyme grabs on and slices the drug resistance RNA in two. The EGS emerges unchanged and binds to other copies of the drug-resistant RNA template. Altman and his colleagues created EGSs specific to two antibiotics, chloramphenicol and ampicillin, and effectively resensitized a resistant Escherichia coli strain to both drugs.

If EGSs can be adapted to reverse drug resistance in human bacterial and viral infections, they could revitalize many old and relatively ineffective antibiotics, says Altman. Allen Goldberg, chair of Innovir, a New York-based biotech company that has licensed EGS technology, says researchers there have already had some success at EGS treatments of mice infected with a drug-resistant hepatitis virus. But researchers still have to find a safe and easy way to put an EGS into human cells, a feat that could take several years of work. "At this point, these are only pipe dreams," he says.

Mitchell Cohen, a microbiologist at the Centers for Disease Control and Prevention, in Atlanta, says that although he finds the EGS approach to drug resistance "very clever," in the long run, it may be no more effective than another new antibiotic. "This method doesn't get around the problem of selective pressure." Bacteria will probably evolve a way around it, he says.

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