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Forcing Pathogens to Compete for Resources May Help Thwart Drug Resistance

Could forcing pathogens to compete for resources be the key to fighting drug-resistance and extending the lives of existing drugs?

The results of a new study from investigators at Pennsylvania State University in Pennsylvania provide strong evidence to support that forcing pathogens to compete for resources in the human body may help prevent the emergence of drug resistance and extend the life of existing drugs.

Drug resistance emerges when a genetic mutation arises in a pathogen that enables it to thwart the mechanisms of a drug designed to kill it. One mutant pathogen can survive and replicate into billions of superbugs, capable of surviving against even the strongest medications. However, although these pathogens may be strong in resistance, that strength comes at the expense of their ability to efficiently acquire the resources they need for survival, leaving room for the susceptible pathogens to get to the resources first.

Knowing that pathogens compete, the Penn State investigators devised experiments in which they controlled the availability of much-needed resources for a particular pathogen to determine if this had an impact on the pathogen’s ability to resist a drug designed to kill it.

For the experiments, the investigators manipulated the presence of a nutrient used by malaria parasites, in the drinking water of mice infected with drug-sensitive malaria parasites. According to a press release, one group of infected mice were given water containing the nutrient, and another group of infected mice was given water without the nutrient. After testing, the investigators found that when treated with traditional treatment, 40% of mice who were provided with the nutrient failed treatment as resistant strains of the parasite emerged. Conversely, none of the mice in which the nutrient was withheld failed traditional treatment. The investigators concluded that by limiting access to the crucial nutrient, they could stave off the emergence of drug resistance.

To confirm that these outcomes were the result of forcing pathogens to compete and not because of another effect of controlling access to the nutrient, the investigators infected another set of mice with only drug-resistant strains of the parasite. They then limited the crucial nutrient and treated the mice with traditional treatment. Without having to compete against susceptible parasites for the nutrient, the resistant parasites survived.

However, when another set of mice were infected with both susceptible and resistant parasites, and the nutrient was limited, the resistant parasites stopped growing after traditional treatment. This effect occurred even when resistant parasites initially outnumbered susceptible ones.

According to Andrew Read, PhD, Evan Pugh Professor of Biology and Entomology and Eberly Professor of Biotechnology at Penn State, and senior author of the study, “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 in great numbers. 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.”

Given pathogens’ ability to quickly evolve to anything that is thrown at them, Contagion® reached out to the investigators to inquire if the act of limiting resources would create ‘super-duper’ superbugs, capable of resisting treatments while also using fewer resources to survive. According to study co-author, Nina Wale, PhD, postdoctoral research fellow at the University of Michigan, probably not. “Resistant parasites are much more reliant on the resource we manipulated than susceptible parasites,” she explained. “Hence, the only parasites that have a strong incentive to evolve around their need for the resource and become 'super-duper' are resistant parasites. Since resistant parasites make up a tiny portion of the parasite population and are very weak competitors, it will take a very long time for a mutant that can 'get around' their need for the resource to pop up.”

“Even if we manipulated a resource that was essential for both susceptible and resistant parasites,” Dr. Wale continued, “we think pathogens may find it very difficult to evolve around resource limitation or they would have done so already. Pathogens have been competing for resources for a long time and so there has always been a strong incentive for them to get around their requirement for essential nutrients. The fact that parasites still require certain nutrients suggests that they haven't (and perhaps can't) evolve around their need for certain resources.”

She added the small caveat that, “of course, as with any new intervention, it will be very important to investigate empirically the long-term consequences of it.”

According to the press release, “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.” Learning what resources pathogens need could be particularly helpful in situations where there are not many choices available in terms of treatment.

Dr. Reed explained, “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." He continued, “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.”