The history of antibiotics is a history of running in place. Two years after the first of these life-saving drugs—penicillin—was mass-produced, bacteria that resisted the drug became widespread, too. With grim inevitability, the same events have unfolded for every other drug. Every time scientists identify a new substance that can hold back the tide of infectious disease, resistant superbugs surge over that barrier in a matter of years.
The evolution of drug-resistant microbes is unavoidable, but it’s not instantaneous. And one might reasonably wonder why. Microbes have been around for billions of years. They have had, quite literally, all the time in the world to invent every possible biochemical trick, including ways of defusing antibiotics that they themselves use to kill and suppress each other. So why aren’t all microbes already resistant to all drugs?
“The reason is that resistance, like any superpower, comes at a cost,” says Nina Wale, from the University of Michigan. For example, microbes could create pumps that flush out any killer drugs, but those pumps cost energy to build and maintain. These costs mean that, under normal conditions, resistant microbes grow more slowly than their susceptible peers, and are almost always outcompeted. But antibiotics tip the balance of this competition by finally giving the resistant microbes a huge advantage; their susceptible rivals die off, and they can finally take over.
“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.
Of course, it’s possible that microbes will evolve to resist the resource limiters too. But Wale thinks that’s unlikely. Usually, microbes evolve to resist drugs by getting rid of them, neutralizing them, or changing the molecules that they are designed to attack. But those solutions “wouldn’t work against not being given something,” Wale says.
If the approach pans out more broadly, it might give us more options for controlling infectious diseases, beyond just developing more antibiotics. That task has become increasingly difficult. Only a few new antibiotics are in development, and no major new types have emerged for decades. But there are plenty of potential resource-limiting drugs around. They’re often ignored because they don’t kill microbes outright, but they don’t need to be lethal to thwart the emergence of resistance. If scientists can identify these substances, and pair them with existing antibiotics, they could prolong the usefulness of our current arsenal.
“It’s going to be very challenging to find these types of [resource-limiting] compounds,” says Tara Smith, from Kent State University. For example, scientists have long talked about using substances that soak up the metals that microbes require, but that idea “is still more theoretical than practical.” Still, “it’s a good example of the outside-of-the-box thinking we need to preserve antimicrobials.”
“This idea of having something that goes along with an antibiotic and reduces the likelihood of resistance is a very productive field,” says Ramanan Laxminarayan, from the Center for Disease Dynamics, Economics, and Policy. Some groups are working on substances that stop antibiotics from reaching the gut, and fomenting the evolution of resistant superbugs there. Others are developing chemicals that attack resistance genes directly, transforming superbugs back into their civilian alter egos. “These are all different strategies to just coming up with new antibiotics, and I think this is obviously the right way to go,” Laxminarayan says.
“This should certainly be at the forefront of the strategies we test and employ,” says Pamela Yeh from the University of California, Los Angeles. “I think our long battle with antibiotic resistance show us that we'll continue to lose ground against resistant pathogens if we don't consider the environment of the pathogen along with the pathogen itself.”
