If you’re not worried about antibiotic resistance, you probably don’t know enough about it. Before antibiotics, many infections we now consider easily treatable were life threatening. Childbirth was a gamble. Now, our reckless use of antibiotics may be supercharging pathogens and making them immune to treatments.

But it’s not just antibiotics, apparently. In a startling discovery that could reshape our understanding of antimicrobial resistance, a team of Australian researchers has found that two of the world’s most common over-the-counter painkillers (ibuprofen and acetaminophen) can dramatically accelerate the evolution of antibiotic resistance in Escherichia coli, a common bacterium responsible for a host of human infections.

The study, published in npj Antimicrobials and Resistance, highlights a previously overlooked pathway for the creation of superbugs. It suggests that the problem isn’t just the antibiotics we use but the entire cocktail of medications swirling in our bodies.

Antibiotics and Us

Antimicrobial resistance is one of the gravest threats to global public health. For decades, we have lived in a golden age of medicine, wielding powerful antibiotics to keep pathogens at bay. But the bacteria are fighting back. They are evolving, swapping genes, and developing defenses faster than we can invent new drugs to fight them. The crisis is no longer a distant threat; it is here.

In 2019 alone, an estimated 4.95 million deaths were associated with antimicrobial resistance. Without effective antibiotics, cornerstone procedures of modern medicine — from routine surgeries and C-sections to chemotherapy and organ transplants — would become lethally dangerous.

The primary culprit in this story has been the overuse and misuse of antibiotics themselves, in both medicine and agriculture. Every time we use an antibiotic, we apply powerful selective pressure, killing off the susceptible bacteria and leaving only the strongest, most resistant ones to survive and multiply. This is particularly true if we don’t follow the prescription. But what if other, seemingly harmless drugs were acting as accomplices?

To investigate this, the team looked at the human gut.

Our gut is a bustling metropolis of trillions of microbes, a complex ecosystem where bacteria, viruses, and fungi live, compete, and evolve. It is also the primary processing plant for everything we ingest, including medicine. When a person takes multiple drugs (a phenomenon known as polypharmacy, which is increasingly common, especially among the elderly) their gut becomes a chemical soup. The Australian researchers wanted to know what happens when common bacteria are left to swim in that soup.

They took two strains of E. coli, a standard lab strain and a clinical strain isolated from a resident of an elder care facility, and exposed them to the antibiotic ciprofloxacin. Ciprofloxacin is a common antibiotic, frequently used to treat urinary tract infections. These infections are rampant in residential elder care facilities. In parallel, they added one of nine different non-antibiotic medications that are also commonly used in these facilities. These included painkillers like ibuprofen, diclofenac and acetaminophen, the diuretic furosemide, and the cholesterol drug atorvastatin. They used concentrations of these drugs specifically calculated to mimic what would be found in the human intestine after a person takes a standard dose.

The results were striking. When exposed to the antibiotic alone, the bacteria, as expected, began to develop resistance. But when ibuprofen or acetaminophen were added to the mix, the mutation frequency (the rate at which resistant superbugs appeared) shot through the roof. For the lab strain of E. coli, ibuprofen caused a nearly 15-fold increase in the number of resistant mutants compared to the antibiotic alone. Acetaminophen caused a nearly 6-fold increase. The effect was just as significant in the clinical strain isolated from the human gut. The painkillers were turbocharging the bacteria developing resistance.

We’re Breeding Our Next Generation of Killers

The researchers didn’t stop here. They used whole-genome sequencing to look inside the bacterial DNA to pinpoint the exact mutations that had transformed them. They discovered a sophisticated, two-pronged strategy that the bacteria were using to fend off the antibiotic attack.

The first line of defense involved mutating the antibiotic’s primary target. Ciprofloxacin works by attacking and disabling a crucial bacterial enzyme called gyrA, which helps manage the coiling and uncoiling of DNA. Think of it as a specific key (the antibiotic) designed to fit into a specific lock (the enzyme), jamming the machinery and killing the bacterium. Sequencing revealed that many of the highly resistant mutants had developed mutations right in the gyrA gene.

But that’s just half of the story.

The second, and perhaps more insidious, mechanism involved the bacteria’s own defense systems: efflux pumps. Bacteria are covered in tiny molecular pumps that act like microscopic bouncers, actively identifying and ejecting toxic substances like antibiotics from inside the cell. The primary efflux pump in E. coli was mega-activated in mutants, constantly pumping the antibiotic out and keeping it below the lethal threshold. This allowed the bacteria to survive and thrive in an otherwise deadly environment.

These overactive pumps are not picky. They are known to eject a wide variety of compounds, not just ciprofloxacin. And indeed, when the researchers tested their new mutants against other classes of antibiotics, they found they had developed cross-resistance. Remarkably, the most hyper-resistant mutants often had developed both types of mutations.

While this study has its own limitations, it’s an important wake-up call. It shows that we’ve woefully underestimated the complexity of antibiotic resistance, and how other factors may play a role. This isn’t about telling people to stop taking painkillers. It’s about recognizing that our bodies are complex ecosystems and that every pill we swallow contributes to the chemical environment that shapes the evolution of the microbes within us.

This new knowledge demands a more holistic and cautious approach to prescribing, urging us to consider not just the effect of a single drug, but the powerful, and potentially perilous, effect of the entire medicine cabinet.