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To fight drug resistance, make germs compete

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Harnessing competition among pathogens inside a patient could help fight drug resistance, new research suggests.

Researchers found that limiting a much-needed resource could pit pathogens against one another and both extend the life of existing drugs to which pathogens are already resistant and prevent resistance to new drugs from emerging.

“Drug resistance is hindering efforts to control HIV, tuberculosis and malaria, which collectively kill nearly 3 million people worldwide every year,” says lead author Nina Wale, a postdoctoral researcher at the University of Michigan, who conducted the work while a graduate student at Penn State. “It also complicates recovery from major surgeries and cancer chemotherapy.”

‘A big problem’

“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? We could use other drugs, but other drugs may not be available, and developing new ones is a lengthy and expensive process.

limiting pathogen resources (fighting drug resistance)
(Credit: U. Michigan)

“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,” says Wale, who works in the ecology and evolutionary biology department in the laboratory of Meghan Duffy at the University of Michigan.

Drug resistance originates when a pathogen—such as a parasite, virus, or bacterium—develops a genetic mutation that allows it to avoid being killed by the drug.

Even if only one individual pathogen has this mutation, as is frequently the case when resistance first arises, that one individual can replicate into a population of billions once it survives drug treatment. But resistance often comes with a cost, and drug-resistant pathogens often do not acquire certain resources as efficiently as other pathogens, or they may require more of the resource.

“In the absence of drug treatment, the only thing that stops resistant pathogens from spreading is competition with the pathogens that are sensitive to drug treatment,” says senior study author Andrew Read, a professor of biology and entomology and of biotechnology at Penn State.

“We’re utilizing the natural force of competition to control the resistant ones and using conventional drugs to treat the sensitive ones,” he says.

Parasites go head to head

The researchers manipulated a nutrient in the drinking water of mice that malaria parasites use during an infection—just as a gardener might manipulate nutrients through fertilizers to favor certain plants. Researchers used this dietary intervention alongside traditional drugs as a sort of combination therapy.

“We treated mice infected with drug-sensitive malaria parasites with traditional drugs,” Wale says. “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 researchers then confirmed that their results were due to competition among parasites and not some other effect of limiting the nutrient. When researchers infected drug-treated mice with resistant strains only and the nutrient was limited, the resistant parasites survived.

But when they infected drug-treated mice with both sensitive and resistant parasites, limiting the nutrient stopped resistant parasites from growing at all—even when resistant parasites were initially present at far greater numbers than when they typically first appear in a host.

New direction

“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,” Read says.

“People have already been looking for weak points of resistant pathogens, but they do it in the absence of susceptible ones,” he explains. “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.”

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This work suggests a new direction of study that would allow researchers to capitalize on the natural competition between pathogens to control the emergence of drug resistance.

For infections like tuberculosis and malaria, where drug-resistant strains to traditional drugs already exist, researchers must next identify a resource or nutrient for which drug-resistant strains have greater needs than sensitive strains. Then, they have to confirm that limiting the resource would lead to the elimination of resistant strains, determine the most effective intervention strategy to remove the resource, and pinpoint the ideal timing of the intervention. For an infection where a new drug is being developed, these questions could be addressed during the drug development phase.

“Researchers already go to great lengths to identify drug resistance as a routine part of drug development,” Read says.

“You could work the development of a resource-limiting intervention into that drug development pipeline. The initial cost would increase, but after that relatively small initial investment, you might be able to extend the lifetime of a drug. It costs a hundred million dollars or more to bring a new drug to market, so the payoff could be quite big,” he says.

“Typically if a physician detects drug resistance in an infection, they won’t use that drug. And that’s okay if you’ve got another option. But if you haven’t got another option, this is the sort of manipulation that would allow you to treat the patient even when resistance is there.”

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Researchers describe this ecological approach to drug resistance in a new paper in the Proceedings of the National Academy of Sciences.

In addition to Wale and Read, the research team includes researchers from Penn State and Queen’s University. The Institute of General Medical Science funded the work.

Source: University of Michigan