Divide and conquer: Pitting pathogens against each other helps fight drug resistance

Bacteria are becoming increasingly resistant to our best drugs and antibiotics, and if we aren’t careful we could prescribe ourselves into a future where even the most routine treatments and surgeries become deadly again. Now, researchers at the University of Michigan have come up with a novel way to fight back: by pitting pathogens against each other, then using drugs to wipe out the leftovers.

Last year, a UK governmental report warned that antibiotic-resistant “superbugs” could kill 10 million people each year by 2050, and outlined ways we can prevent that nightmare scenario from playing out. Developing new drugs is a priority, but that takes time and resources and eventually bacteria will just become resistant to those too. In the meantime, to squeeze the most use out of existing drugs we need to change the way we use them, cut back on prescriptions, and find new ways to administer them.

Pathogens like bacteria or viruses become drug resistant by evolving advantageous genetic mutations, and from there, it only takes one resistant bug to replicate into billions. But the Michigan researchers realized they could turn natural selection into a weapon. Instead of targeting the bacteria themselves, the scientists reduced the levels of a certain nutrient that the bugs rely on, and the sudden scarcity caused the pathogens to turn on each other.

In a stroke of luck, the researchers point out that drug-resistant pathogens usually aren’t as efficient at acquiring those nutrients, meaning they’re the first to die off in a drought. With just the non-resistant bugs left, doctors can then clear the infection by administering the drug as normal.

“We are faced with a big problem: What can we do when a patient is infected with a drug-resistant pathogen, which will cause treatment to fail?” says Nina Wale, lead author on the new study. “We could use other drugs, but other drugs may not be available, and developing new ones is a lengthy and expensive process. By taking advantage of competition between parasites inside a host, we managed to use an existing drug to successfully treat an infection, even when drug-resistant parasites were already there.”

To test the idea, the Michigan team worked with mice infected with malaria, and identified a key nutrient that the malaria parasite needs to thrive. Some mice were given more of that nutrient in their drinking water, while others were given water with reduced amounts of the same nutrient. Both groups of mice were then treated with the same malaria drugs.

“We treated mice infected with drug-sensitive malaria parasites with traditional drugs,” says Wale. “When mice were given the nutrient, the treatment failed in 40 percent of the mice, and we confirmed by a variety of tests that this was because drug-resistant strains had popped up. But when the nutrient was limited, the infection did not rebound in a single mouse. So by limiting this nutrient, we prevented the emergence of drug resistance.”

The next step was to check whether competition between the bacteria really was responsible for the improvement, or if the nutrients themselves had some unknown side effect. To test that, the team infected some mice with only resistant bacteria, and others with both resistant and non-resistant bacteria. Sure enough, the treatment only worked in the mice with both types of bugs.

“This study is a proof-of-principle that an ecological manipulation can make it possible to continue using a drug even when resistant pathogens that would otherwise cause a treatment failure are present at great numbers,” says Andrew Read, senior author of the study. “People have already been looking for weak points of resistant pathogens, but they do it in the absence of susceptible ones. Our work shows that studies that do not involve this competition aspect are missing the natural force that keeps resistance under control, and that is missing a huge amount of potential for manipulation.”

This isn’t the first time bacterial espionage has been used in the war against drug resistance. Last year, to fight off a strain of multi-drug-resistant bacteria scientists from London injected patients with other bacteria that naturally prey on the dangerous species. It’s encouraging to know that scientists are getting creative in an effort to solve the dire issue of drug resistance.