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Pathogen vs. pathogen to prevent drug resistance
January 7, 2018, 1:53 pm

Limiting a much-needed resource could lead to pathogens competing against one another and thereby prevent the emergence of drug resistance, say researchers at Penn State University in the US. The team demonstrated that harnessing rivalry among pathogens inside a patient could extend the life of existing drugs where resistance is already present and prevent resistance to new drugs from emerging.

Drug resistance is hindering efforts to control HIV, tuberculosis and malaria, which collectively kill nearly three million people worldwide every year. It also complicates recovery from major surgeries and cancer chemotherapy. When a patient is infected with a drug-resistant pathogen, one alternative is to try other drugs, or unrealistically, wait for a new drug to be developed.

By taking advantage of competition between parasites inside a host, the team managed to use an existing drug to successfully treat an infection, even when drug-resistant parasites were already there.

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. But this resistance often comes with a cost, as 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.

By utilizing the natural force of competition, the team was able to control the resistant ones and to use conventional drugs to treat the sensitive ones. The researchers manipulated a nutrient in the drinking water of mice that is used by malaria parasites during an infection. This dietary intervention was used alongside traditional drugs as a sort of combination therapy.

The team treated mice infected with drug-sensitive malaria parasites with traditional drugs. When mice were given the nutrient, the treatment failed in 40 percent of the mice, and the researchers confirmed 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.

Moreover, when drug-treated mice were infected only with resistant strains and the nutrient was limited, the resistant parasites survived. But when drug-treated mice were infected 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.

"This study is a proof-of-principle that an ecological manipulation can make it possible to continue using a drug," said a team member, "even when resistant pathogens that would otherwise cause a treatment failure are present at great numbers. 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; 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.

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