BALTIMORE, Md.—“The drug you design ten years from now may already be obsolete,” said Ivan Erill, Ph.D., professor of biological sciences at the University of Maryland, Baltimore County.
In a new study published January 10th in Frontiers in Microbiology, Erill and colleagues described how bacteria that existed hundreds of millions of years ago were already resistant to an antibacterial drug not invented until the 1930s. Once farmers began using the new class of drugs in agriculture, resistance spread quickly. As the bacteria were exposed to the drugs on a large scale in soils and waterways, antibiotic-resistant strains began appearing in hospitals within a decade.
How is this possible? Antibiotic resistance has much deeper roots than most people realize, Erill explained. Many antibiotics used to treat bacterial infections today are based on molecules bacteria naturally produce to out-compete their neighbors. “Your competitors are not just going to stand by,” continued Erill, “so over millions of years they are going to develop resistance. That’s a given.”
The drugs featured in this research are not natural antibiotics, they’re synthetic compounds produced by humans - sulfonamides. “With synthetic drugs, that’s a different picture altogether,” Erill noted. “It’s not a given that you would find resistance.” That’s why the research team was surprised when they did—hundreds of millions of years before the drugs were invented.
Sulfonamides target an enzyme involved in a pathway necessary for DNA synthesis. If an organism can’t replicate its DNA it can’t reproduce, so its population quickly dwindles to nothing. The bacteria that are resistant to sulfonamides have modified genes for the target enzyme, called sul genes, which allow the bacteria to continue reproducing in the presence of the drug.
Most sulfonamide-resistant bacteria have sul genes in what are called mobile elements—small segments of DNA that can easily jump from one individual or species to another. Erill and his colleagues used computational tools to figure out which bacteria species had sulfonamide-resistance genes in their chromosomes instead of in mobile elements, indicating that they were the original sources of the resistance. They showed that two groups of bacteria harbor chromosomal sul-like genes.
“You can use algorithms to reconstruct the most likely evolutionary history that explains the development of sulfonamide resistance,” stated Erill.
Those algorithms allowed researchers to confirm that the resistance existed 500 to 600 million years ago. To further verify their results, the researchers inserted copies of the chromosomal sul-like genes into bacterial cells in the lab. When exposed to sulfonamides, the cells grew just fine, confirming that the genes confer resistance.
“How can you explain that bacteria 500 million years ago were resistant to a substance that didn’t yet exist?” asked Erill.
While there’s a small chance some organism was producing a sulfonamide-like compound hundreds of millions of years ago and resistance evolved in response to that pressure, Erill and his team put forth a different argument. “There is an enormous amount of bacterial genetic diversity,” Erill said.
“Resistant variants of the antibacterial target could be present in the global genetic pool even before microbes are exposed to them,” added Miquel Sanchez, a Ph.D. student at the Universitat Autònoma de Barcelona and the first author on the paper.
The reason that these two bacterial groups were resistant to a compound that had never existed? According to Erill, “We argue that this is just pure chance.”
This research has big implications for the development and use of future antibiotics. If scientists develop a new antibiotic, “it is well possible that there might be one bacterium in the world that is already resistant,” Erill mentioned. With conservative use of the antibiotic in human patients, though, it’s unlikely that particular bacterium would ever be exposed to the antibiotic and spread its resistance.
However, “if you overuse the drug, especially in an agricultural setting, where the drug slowly permeates into the soil, waterways, and underground water reservoirs,” you will be exposing “this huge population of bacteria that otherwise would never be bothered by antibiotics or synthetic drugs,” Erill continued. And based on the team’s analysis, if the one bacterium that is already resistant is exposed to the drug, the resistant variant will jump to other species within years.
“For me, it’s especially a warning against using antibiotics in farm settings,” Erill stressed. New drugs are typically tested using disease-causing bacterial species, “but maybe that’s not enough. Maybe you should do broader testing, especially on the non-usual suspects, like soil bacteria.”
Erill also pointed out that the new finding points toward using combination therapies more often. A bacterium in nature might harbor a chance resistance to one compound it’s never encountered, but it’s unlikely to be resistant to two. If doctors use two drugs at once, it’s likely that one of the drugs will kill the bacteria, preventing it from spreading its resistance to the other drug. These new research findings could affect how well superbugs are kept at bay and the effectiveness of new antibiotic treatments.
