How antidepressants help bacteria resist antibiotics

Colored scanning electron micrograph of the rod-shaped, gram-negative bacterium Escherichia coli

In the presence of antidepressants, the gram-negative bacteria, E. coli, can ward off antibiotics.Credit: Steve Gschmeissner/Science Photo Library

The emergence of antibiotic-resistant disease-causing bacteria is often attributed to antibiotic overuse in humans and livestock. But researchers have focused on another potential driver of resistance: antidepressants. By studying bacteria grown in the lab, a team has now tracked how antidepressants can cause drug resistance1.

“Even after a few days of exposure, bacteria develop drug resistance, not just to one but to multiple antibiotics,” said senior author Jianhua Guo, who works at the Australian Center for Water and Environmental Biotechnology at the University of Queensland in Brisbane. This is both interesting and scary, he says.

Antibiotic resistance is a major threat to public health worldwide. In 2019, an estimated 1.2 million people died as a direct result2and that number is expected to rise.

Early clues

Guo became interested in the possible contributions of nonantibiotics to antibiotic resistance in 2014 after work from his lab found more antibiotic resistance genes circulating in samples of domestic wastewater than in samples of hospital wastewater, where antibiotic use is higher.

Guo’s group and other teams also noted that antidepressants — which are among the most commonly prescribed drugs in the world — killed or stunted the growth of certain bacteria. They elicit an “SOS response,” Guo explains, activating cellular defense mechanisms that in turn help the bacteria better survive subsequent antibiotic treatment.

The group reported this in a 2018 paper Escherichia coli became resistant to multiple antibiotics after exposure to fluoxetine3, which is commonly sold as Prozac. The latest study examined 5 other antidepressants and 13 antibiotics from 6 classes of such drugs and examined how resistance in E coli developed.

In bacteria grown in well-oxygenated laboratory conditions, the antidepressants caused the cells to produce reactive oxygen species: toxic molecules that activated the microbe’s defense mechanisms. This especially activated the bacteria’s efflux pump systems, a common expulsion system that many bacteria use to eliminate various molecules, including antibiotics. This likely explains how the bacteria were able to resist the antibiotics without having specific resistance genes.

But exposure of E coli antidepressants also led to an increase in the microbe’s mutation rate and the subsequent selection of several resistance genes. Although in bacteria grown under anaerobic conditions, levels of reactive oxygen species were much lower and antibiotic resistance developed much more slowly.

In addition, at least one antidepressant, sertraline, promoted the transfer of genes between bacterial cells, a process that can accelerate the spread of resistance through a population. Such transfer can occur between different types of bacteria, allowing cross-species resistance – including from harmless bacteria to pathogenic bacteria.

Growing recognition

Kiran Patil, who studies microbiome-chemical interactions at the University of Cambridge, UK, says there has been growing awareness over the past five years that many non-antibiotic drugs targeting human cells can also attack bacteria and contribute to antibiotic resistance . “The strength of the study is the mechanistic details,” says Patil.

Lisa Maier, who works at the University of Tübingen in Germany and studies interactions between drugs and the microbiome, says that to understand how antidepressants can boost antibiotic resistance, researchers need to determine which molecules the drugs target in the bacteria and the effects of the drugs. drugs on a wider variety of clinically relevant bacterial species. In 2018, Maier and her colleagues examined 835 drugs that did not target microbes and found that 24% inhibited the growth of at least one strain of human gut bacteria4.

Patil and Maier say it’s important to collect evidence to assess the real-world impact of antidepressants on drug resistance, for example whether antidepressants encourage the accumulation of antibiotic-resistant bacteria, particularly disease-causing bacteria, in humans, animals or the environment.

While significant amounts of antidepressants have been found in wastewater, reported levels often fall below the concentrations at which Guo’s group saw significant effects in E coli. But concentrations of some of the antidepressants that had strong effects in this study are expected to be reached in the colons of people taking the drugs.

Follow-up studies

Maier says several studies are now linking antidepressants and other non-antibiotic drugs to changes in bacteria and preliminary studies have provided the “first hints” about how such drugs may affect the microbiomes of people who take them.

But in healthy people E coli is mainly found in the large intestine, where conditions are anaerobic, meaning the process described in the paper may not occur to the same extent in humans, says Maier. Future studies should use bacterial growth conditions that model sites on which antidepressants could act, says Patil.

Guo says his lab is now looking at the microbiomes of mice given antidepressants. Early, unpublished data suggests the drugs may alter the animals’ gut microbiota and promote gene transfer.

But Guo and Maier warn people not to stop taking antidepressants based on this research. “If you have depression, it should be treated in the best possible way. After that, the bacteria come second,’ says Maier.

Although researchers and pharmaceutical companies need to quantify the contribution of non-antibiotic drugs to antibiotic resistance, Guo says. “Non-antibiotic drugs are a big concern that we shouldn’t overlook,” he says.

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