A Bold New Strategy for Stopping the Rise of Superbugs
Scientists have pinpointed a molecule that accelerates the evolution of drug-resistant microbes. Now they’re trying to find a way to block it.
The British chemist Leslie Orgel reputedly once said that “evolution is cleverer than you are.” This maxim, now known as Orgel’s Second Rule, isn’t meant to imply that evolution is intelligent or conscious, but simply that it’s inventive beyond the scope of human imagination. That’s something people who fight infectious diseases have been forced to learn again and again.
Over the past 90 years, scientists have discovered hundreds of antibiotics—microbe-killing drugs that have brought many pernicious diseases to heel. But every time researchers identify a new drug, bacteria inevitably evolve to resist it within a matter of years. We thrust; they parry. Now, with the flow of new antibiotics having dried up for decades, our stalemated duel with infectious bacteria threatens to end in outright defeat. Superbugs are ascendant around the world, including those that resist all commonly used drugs.
Houra Merrikh from the University of Washington thinks she has found a way of improving our odds. She and her team have identified a bacterial “evolvability factor”—a molecule these microbes need to rapidly evolve into drug-resistant strains. If she can find a way to block this molecule, she could pave the way for a new kind of drug: an anti-evolution drug that doesn’t kill microbes, but stops them from powering up into superbugs (or at least delays the process). “They have this way of turning evolution on,” Merrikh says. “And if they can turn it on, we can turn it off.”
Merrikh didn’t set out to beat antibiotic resistance. Originally, she didn’t even know she would be a scientist. She and her family fled from Iran when she was 3, settling in Turkey to avoid the war with Iraq. At 16, at her parents’ insistence, she moved to Texas to find an education. Stuck in an unfamiliar country with neither family nor money, she worked several poorly paid jobs to pay her way into college. Once there, she found her calling in biochemistry. Within 16 years, she was running her own lab.
At first, she studied the inner lives of bacteria, and the ways in which they copy their DNA and switch on their genes. That work bore unexpected fruit in 2015, when her team showed that a bacterial protein called Mfd can increase the rate at which genes mutate—that is, change their DNA. It was an unusual discovery. Other researchers had billed Mfd as a DNA-repairing protein, which would prevent mutations rather than promote them. But the more Merrikh studied Mfd, the less sense that made. For example, when her colleague Mark Ragheb removed it from bacteria, the microbes’ mutation rates fell by 50 to 80 percent.
That’s a big deal. Mutations are the fuel for evolution. If enough bacteria accumulate enough changes to enough genes, chances are that one of them will randomly acquire the ability to shrug off an antibiotic. So, in theory, if you can reduce mutation rates, you should also be able to delay the rise of resistance. The team proved this by exposing strains of Salmonella, with and without Mfd, to a battery of common antibiotics. After several generations, it found that strains that still had Mfd were between 6 and 21 times more resistant to the drugs than those without the protein.
The team repeated the experiment with other species of bacteria, and got results that were either similar or even more striking. For example, when it tested the bacterium behind tuberculosis, it found that Mfd-carrying strains became up to 1,000 times more resistant to antibiotics than the Mfd-less ones. “It applied to every bug we looked at and every antibiotic we tested,” Merrikh says. “The global nature of the effect is the most striking thing.”
That the loss of Mfd should be so universally debilitating makes sense because the protein itself is almost identical in a wide range of microbes, even distantly related ones. Usually, different bacteria will have their own takes on commonly shared proteins, like people speaking distinct dialects of a common language. But when it comes to Mfd, all bacteria essentially speak in the same accent. “Clearly this thing has a really important role,” Merrikh says.
Tami Lieberman from MIT says this approach has uses beyond stymieing superbugs. Many scientists are trying to genetically modify bacteria for industrial purposes, to pump out medicines or fuels. But those engineered microbes can evolve into obsolescence by picking up mutations that inactivate the foreign genes within them. “A synthetic biologist might consider deleting Mfd in their engineered strains to prolong their utility,” Lieberman says.
Merrikh, meanwhile, is focused on the antibiotic problem. “If you look at the history of antibiotics, in every single case, as soon as the drug hits the market, resistance arises. So the strategy of making new drugs isn’t ever going to work,” she says. “Our idea is that before the next drug hits the market, let’s have an anti-evolution drug to give alongside it, to at least delay the development of resistance.”
“All steps forward are good, and I think this is a great one,” says Michael Johnson from the University of Arizona. The challenge, he says, is to find a fast and efficient way of screening libraries of chemicals for drugs that can actually disable Mfd in the body of a human patient. Merrikh’s team is already on the case.
But wouldn’t bacteria eventually evolve resistance to the anti-Mfd drugs? “The chances are very low,” Merrikh says. “You’re turning off the mechanism that would do that in the first place.”
“I’m skeptical,” says Tara Smith from Kent State University. She has heard claims about evolution-proof drugs before, and they almost always fizzle out. Some scientists argued that bacteria were unlikely to evolve resistance to small molecules called antimicrobial peptides, because they were so diverse. One even put a bet on it—and lost. Others suggested that bacteria were unlikely to evolve resistance to viruses called phages, and were repeatedly proven wrong.
Still, Smith says that Merrikh’s claims are “much more measured” than those from other researchers who have forgotten Orgel’s Second Rule. And “it’s one of those outside-the-box ideas that we need because, clearly, the usual model of antibiotic discovery, approval, use, and resistance isn’t working,” she says.
Many other scientists are also trying to find anti-evolution drugs. For example, Rahul Kohli from the University of Pennsylvania, is trying to disable the appropriately named “SOS response”—a system that bacteria use to cope with stress, and that also increases their mutation rates. His team has already identified drugs that can block that system.
The problem with disabling the SOS system, Merrikh says, is that bacteria become “very, very sick,” even in the absence of antibiotics. That creates an enormous incentive to evolve some kind of countermeasure. And that’s not the case with Mfd. When her team deleted it, the bacteria were nigh-indistinguishable from normal cells. That should reduce the impetus for bacteria to evolve their way around the hypothetical anti-evolution drug.
It might also be difficult to convince agencies like the FDA to approve anti-evolution drugs. It’s easy enough to prove that a drug can kill bacteria in a clinical trial, “but if you have a drug that prevents the development of resistance, going through clinical trials is going to be harder,” Merrikh says. “The effect is only going to be apparent in a population over many years. How to get a drug like that into the market is a big challenge.”