Medical experts have been powerless to stop the rise of antibiotic-resistant bacteria and are increasingly desperate to develop novel drugs. But a new study finds that smarter use of current antibiotics could offer a solution. Researchers were able to keep resistant bacteria from thriving by alternating antibiotics to specifically exploit the vulnerabilities that come along with resistance—a strategy that could extend the lifespan of existing drugs to continue fighting even the most persistent pathogens.

The prevailing theory on how resistance develops posits that reckless antibiotic-prescribing practices drive the evolution of resistant microbes. Because bacterial genes mutate at high frequencies, any bacterial population will have many individual microbes carrying different mutations. By chance, one or several may fight off an antibiotic, and those resistant variants will survive to proliferate.

Based on this notion, doctors have long tried to alternate antibiotic drugs to prevent resistance. By limiting exposure to any one drug, they hope to reduce the chance that a single type of resistant bacteria predominates. Once the antibiotic is removed, they expect the nonresistant bacteria to multiply and outcompete the resistant variants, which then naturally die out. This practice assumes, however, that resistant bacteria are less “fit” than other bacteria. In practice, the results of alternating drugs have been mixed, and resistant bacteria often survive.

In the new research, systems biologists Lejla Imamovic and Morten Sommer of the Technical University of Denmark in Lyngby used Escherichia coli to explore how bacteria change when they become resistant to a drug. They found that when E. coli gains resistance to one antibiotic, it also becomes more sensitive others—a phenomenon they call “collateral sensitivity.”

For example, bacteria often become resistant to the antibiotic tetracycline by gaining an efflux pump—a membrane protein that pumps antibiotics and other compounds out of the cell. But the pump also enables compounds to flow in, making the bacteria more sensitive to other antibiotics. Using this knowledge, one could introduce a second antibiotic that flows in via these efflux pumps to kill the resistant variants.

By applying what the authors dub “collateral sensitivity cycling,” doctors could kill resistant bacteria by switching to an antibiotic they have become more vulnerable to because of their resistance to the first drug, Sommer explains. The idea of cycling antibiotics dates back to the 1950s, he says, but fell out of favor after the boom in drug development.

To test the approach, Imamovic and Sommer exposed a lab strain of E. coli to increasing doses of an antibiotic until resistant variants emerged. They then exposed the variants to 23 different antibiotics and profiled their responses: Did they become more or less resistant to each of the 23 drugs? The researchers repeated the experiment with two E.coli strains taken from infected patients. Then they plugged this data into a computer program and identified more than 200 possible drug combinations that doctors could use to achieve collateral sensitivity and wipe out resistant variants. These drugs could be prescribed in cycles as either double, triple, or quadruple treatments, the authors report online today in Science Translational Medicine.

The idea seems so simple, Sommer says, that one reviewer of the paper remarked, “I can’t believe that no-one has done this before.” But Sommer had spent hours searching the literature but had turned up nothing—not a single study that used the idea of collateral sensitivity to choose antibiotics.

“Many people have advocated switching drugs,” says Robert Beardmore, a bioscience mathematician at the University of Exeter in the United Kingdom. “But this shows that you can't just make any old switches. You can take a path of choices to form something like an entire treatment that selects against resistance.”

There is one bit of caution: The researchers have done the tests only in vitro and used only E. coli, Beardmore says. “The acid test will be when these ideas are implemented in vivo.”