Duke University biomedical engineers have uncovered an important link between the spread of antibiotic resistance genes and the evolution of resistance to new drugs in certain pathogens.

Research shows that bacteria exposed to high levels of antibiotics often carry multiple identical copies of protective antibiotic resistance genes. These duplicated resistance genes are often linked to “jumping genes” called transposons that can jump from strain to strain. Not only does this provide a mechanism for resistance to spread, but having multiple copies of a resistance gene can also provide a handle for evolution to develop resistance to new types of drugs.

The findings were published in the journal Feb. 16. Nature Communications.

Early work from the Lingchong Yu lab showed that 25 percent of bacterial pathogens have the ability to spread antibiotic resistance through horizontal gene transfer. They also showed that the presence of antibiotics does not speed up horizontal gene transfer, so there must be something else going on that pushes the genes to spread.

“Bacteria are constantly evolving under many pressures, and the increased transcription of certain genes is like a fingerprint left at the scene, allowing us to identify them,” said Rohan Madam Sethi, a postdoctoral fellow who works in the lab. “Allows to see what kind of functions are developing really fast”. Lingchung UK, James L. Merriam Distinguished Professor of Biomedical Engineering at Duke.

“We hypothesized that bacteria attacked by antibiotics often have multiple copies of protective resistance genes, but until recently we didn’t have the technology to find the smoking gun.”

Traditional DNA-reading technology copies short fragments of genes and counts them, making it difficult to determine whether high concentrations of specific sequences are actually present in a sample or whether the reading process has artificially detected them. is being extended. However, in the past five years, whole-genome sequencing with long-read technology has become more common, allowing researchers to detect high levels of genetic duplication.

In the study, Maddamsetti and co-authors counted the frequency of resistance genes present in samples of bacterial pathogens taken from a variety of environments. They discovered that those living in places with high antibiotic use — humans and livestock — are enriched with multiple identical copies of antibiotic resistance genes, while those in wild plants, animals, soil and water. Such transcripts are rare in living bacteria.

“Most bacteria have some basic antibiotic resistance genes, but we’ve rarely seen them replicate in nature,” you said. “In contrast, we’ve seen a lot of replication in humans and cattle where we’re potentially hammering them with antibiotics.”

The researchers also found that the level of resistance replication was even higher in samples taken from clinical datasets where patients were likely taking antibiotics. This is an important point, they say, because increased replication of antibiotic resistance genes also increases the likelihood of bacteria developing resistance to new types of treatment.

“Making continuous copies of genes for resistance to penicillin, for example, could be the first step towards being able to break down a new type of drug,” said Madam Setti. “It gives evolution more rolls of the dice to find a particular mutation.”

“Everyone recognizes that the antibiotic resistance crisis is growing, and the knee-jerk reaction is to develop new antibiotics,” you added. “But what we find over and over again is that, if we can figure out how to use antibiotics more effectively and efficiently, we can potentially solve this crisis by just developing new drugs. can be solved more effectively.”

“Most antibiotics used in the United States are not used on patients, they are used in agriculture,” you added. “So this is a particularly important message for the livestock industry, which is a major driver of why antibiotic resistance is ever-present and becoming more serious.”

This work was supported by the National Institutes of Health (R01AI125604, R01GM098642, R01EB031869).