Bacteria Can Evolve Resistance to Drugs Before Those Drugs Are Used

A new study turns the history of MRSA on its head.

A petri dish labeled "MRSA"
Lord have MRSA (Fabrizio Bensch / Reuters)

In 1928, after returning from a countryside holiday and examining a stack of petri dishes that he had left in the sink, British chemist Alexander Fleming discovered a new type of bacteria-killing mold. From that mold, he isolated a chemical called penicillin, and ushered in the modern antibiotic era—an age when humans could finally keep infectious diseases at bay. But in 1945, two years after penicillin became widely used and shortly after Fleming won a Nobel Prize for its discovery, he issued a stark warning against overusing these wondrous chemicals. “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism,” he told The New York Times.

His words were prophetic. The year before, scientists had identified penicillin-resistant strains of Staphylococcus aureus—a bacterium that commonly lives on our skin and in our noses, but sometimes causes life-threatening infections. As penicillin became more widely used, these resistant strains also became more common. To deal with these incipient superbugs, scientists turned to methicillin—a chemical relative of penicillin. But its usefulness was also short-lived. A year after it made its way into British clinics in 1959, Margaret Patricia Jevons isolated three strains of methicillin-resistant Staphylococcus aureus, or MRSA.

MRSA is now a global problem, and has become something of a poster child for the superbug threat. It supposedly showed how bacteria can quickly evolve to resist a drug that comes into wide use—a process that’s illustrated in the video below, the second in a series of online films produced by HHMI Tangled Bank Studios, which adapt the stories in my book, I Contain Multitudes.

But the MRSA origin story always had a few glaring plot holes. For a start, the three initial strains of resistant staph all came from patients who had never been exposed to methicillin, and who were treated in a hospital that had only ever used the drug once. On top of that, MRSA appeared in India and some Eastern European countries before those nations started using methicillin. How exactly did the bacteria evolve to resist a drug that they had never actually seen?

Catriona Harkins and Matthew Holden at the University of St. Andrews have the answer, in a study that turns the history of MRSA on its head, and makes it even scarier than before.

They sequenced the DNA of 209 MRSA samples that were collected between 1960 and 1989, including the earliest resistant strains ever identified. By comparing these strains and reconstructing their evolutionary history, the team calculated that they all descended from a common ancestor that first acquired the ability to resist methicillin in 1946—13 years before people started using the drug to treat infections. “Methicillin use was not the original driving factor in the evolution of MRSA as previously thought,” they write.

That original driving factor was, ironically, penicillin. It turns out that mecA, the same gene that allows staph to shrug off methicillin, also confers some measure of resistance to penicillin. When penicillin became widely used in the 1940s, it likely fueled the rise of staph strains that carried mecA, and were already resistant to methicillin. Initially, those strains were rare—despite its benefits, mecA doesn’t spread easily between staph strains, and slows the growth of the microbes that carry it. But as soon as methicillin came into use, the advantages of carrying mecA outweighed the disadvantages, and the gene became more common.

So bacteria can begin evolving resistance to antibiotics that they haven’t even encountered yet. And new drugs can be neutralized by adaptive genes that are lurking in the environment, waiting for the chance to rise to the occasion. As Hsu Li Yang from the National University of Singapore writes, “Antibiotic resistance is a web of unintended consequences, rather than a simplistic cause-effect model that we often find (too much) comfort in.”

We might be able to predict some of these unintended consequences by routinely sequencing the DNA of wild bacteria, identifying the resistance genes that are already out there. “However, this will be difficult because it is not currently possible to confidently predict resistance from genome-sequence data alone,” says Jessica Blair from the University of Birmingham. “We can only detect resistance mechanisms we already know about.”