“That’s our in,” says Wale. “Competition is the force that keeps resistance down in nature. Maybe we can harness that competition to keep them down before they even get going.” She and her colleagues, led by Andrew Read at Pennsylvania State University, have devised a way of preventing the evolution of drug-resistant microbes, by putting them at a competitive disadvantage even when antibiotics are around.
The team proved this concept by studying mice infected with malarial parasites. When Wale and her colleagues treated the mice with the drug pyrimethamine, resistant parasites emerged as expected. But these parasites have a weakness: They’re uniquely hungry for a substance called PABA, which they convert into folate, an essential nutrient. Normally, malarial parasites have other ways of making folate. But these alternatives are shut down by the same mutations that make the parasites resistant to pyrimethamine. So when the parasites evolve to resist the drug, they also become uniquely dependent on PABA for their folate-making needs.
When Wale deprived them of PABA, she not only delayed the emergence of resistant parasites, but completely prevented it. “I was bowled over,” she says. “I plotted the data, and I was sitting on my bed, shaking slightly.”
It’s not that the lack of PABA starves the resistant parasites outright; instead, it makes them less competitive than the susceptible ones. When Wale infected the mice only with resistant parasites, they still became sick. But whenever she infected them with both resistant and susceptible ones, the latter always took over, allowing the pyrimethamine to do its job. That’s encouraging, Wale says, especially because she used tens of thousands of resistant parasites in these competitive experiments—far more than would normally exist when they first emerge in the real world. “Even when the horse has bolted and resistance is already here, by intensifying competition, we can buy ourselves more time,” she says.
Here’s the future that Wale envisions. Rather than simply seeing parasites as targets, we view them as organisms in their own right. We work out the nutrients they need, and how those requirements change as they evolve resistance to drugs. We then identify chemicals that deprive them of said nutrients. These “resource limiters” aren’t meant to kill the parasites, but to put the resistant ones at a perpetual disadvantage so a standard antibiotic can finish off the rest. It’s like “developing anti-spinach” to stop Popeye from becoming strong, Wale says.
“It’s promising,” says Heather Hendrickson, from Massey University. And it’s clearly very effective in this particular setup involving mice and malaria. Whether it would work for other superbugs, including bacteria like staph or E. coli, is a matter of detail. “It will really rely on the strength of competition between the resistant and susceptible versions, and the degree to which we can tip the scale in favor of the drug-susceptible ones,” she says.