Copper antimicrobials can drive antibiotic resistance in bacteria, but there’s a fix, scientists say

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Heavy use of antibiotics has led to bacterial strains that resist them, making some infections difficult to treat. Copper antimicrobials are increasingly used to reduce the emergence of resistant strains. New research shows that heavy use of copper leads to the evolution of copper-resistant E. coli bacteria that can also resist antibiotic drugs. Fortunately, when the use of copper is stopped, bacteria quickly revert to a less-resistant state, suggesting that alternating copper with other antimicrobials could be as effective without driving resistance.​​​ Copper has emerged as an ally in the battle against antibiotic-resistant bacteria. Copper sulfate liquids, for example, have been used since the 1700s to control fungal infections in vineyards, orchards and many other kinds of agricultural settings. Copper surfaces are now often used in health care to help keep facilities sterile. But too much of a good thing can create the very problem it’s trying to solve.

According to new research published in Evolution, Medicine and Public Health, UCLA microbiologists have found that heavy use of copper antimicrobials can also drive antibiotic resistance in bacteria. However, resistance quickly diminishes without copper exposure, suggesting that copper could help reduce antibiotic resistance if alternated with other measures. 

“Some published research shows that switching to copper doesn’t necessarily solve the antibiotic resistance problem. We wanted to know what would happen to bacteria in environments where the heavy use of copper, such as copper-based pesticides and fungicides in agriculture, would place evolutionary pressure on bacteria over time,” said first author Sada Boyd-Vorsah, who led the research as a postdoctoral researcher at UCLA. “We found that bacteria that evolve resistance to copper also become resistant to antibiotics, possibly because they are using biological pathways that help them resist copper to also resist antibiotics.”

Strains of bacteria that cannot be killed by antibiotics pose a serious threat to medicine’s ability to treat infectious diseases. Resistant strains emerge because a few individuals in a bacterial population inevitably survive a strong course of antibiotics and pass on to subsequent generations the traits that helped them stay alive. This process, which biologists call natural selection, ensures that traits that help individuals survive and reproduce will become common enough that the population can persist in the face of pressure from the environment.

Like antibiotics, anything used to kill microbes, which are organisms like bacteria, viruses, yeasts and fungi, can create a hostile environment that drives resistance. This can include chemicals, metals, extreme heat and cold.

“In previous research, our lab showed that the pathway that helps bacteria deal with a very ancient stressor, which is extreme temperature, could be the pathway with which they deal with antibiotics,” said corresponding author Pamela Yeh, who is a UCLA professor of ecology and evolutionary biology. “Because this pathway evolved long ago, it is probably common to many types of bacteria.”

Methodology for the study The team grew colonies of E. coli bacteria in petri dishes and exposed them to copper sulfate, which is a common disinfectant and fungicide. Only 8 of the original 50 populations survived, and subsequent generations were grown from these and exposed again to copper to develop copper-resistant populations. Next, they tested the copper-resistant bacteria with a variety of common antibiotics and found that they also resisted the antibiotics.

Genetic analysis showed that copper-resistant bacteria had evolved 477 genetic mutations that were not found in control populations. Some of these mutations were, not surprisingly, on genes associated with metal resistance, but not antibiotic resistance. The result backs up the Yeh Lab’s previous finding that bacteria use the same pathways to cope with multiple stressors and indicates that antibiotic resistance can be driven by environmental pressures other than antibiotics alone.

“Even though copper antimicrobials are becoming more common, copper-resistant bacteria are not yet common. But it’s useful to know that if they become resistant to copper, they will likely also be resistant to antibiotics. Copper is still a great antimicrobial, but (we) just need to be mindful (of) how we use it, because we don’t want to end up with a similar situation to the one we have now,” said Boyd-Vorsah, who is now a visiting assistant professor at Winston-Salem State University.

To the researchers’ surprise, however, bacteria began to lose their resistance after just seven days without copper exposure. In some populations, resistance fell but still remained high, while in others it fell to baseline levels, showing that there was a certain amount of genetic variability between the resistant populations.

By alternating the use of copper with other antimicrobials, it should be possible to use them to control microbes without driving resistance, researchers said. Although the research was done in E. coli, the researchers said the finding likely applies to many other kinds of bacteria.

“I don’t see any reason why we wouldn’t expect that this is probably a generalizable pattern that could be found across many, maybe even all, species of bacteria because the mechanisms that confer resistance are probably evolutionarily very ancient,” Yeh said.

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