Jianhua Guo is a professor at the Australian Center for Water and Environmental Biotechnology. His research focuses on the removal of contaminants from wastewater and the environmental dimensions of antimicrobial resistance. One of these dimensions is the overconsumption of antibiotics, which promotes resistance to these drugs.
Guo wondered if the same was true for other types of pharmaceuticals. His lab discovered that they definitely did. Specific antidepressants – SSRIs and SNRIs – promote resistance to different classes of antibiotics. This resistance is hereditary over 33 bacterial generations, even once the antidepressant has been withdrawn.
so much work
Antidepressants are among the most prescribed and widely ingested medications. They account for about 5% of the pharmaceutical market share – about the same as antibiotics – and four of the 10 most prescribed psychiatric drugs in the United States.
To assess the potential effects of antidepressants on antibiotic resistance, Guo’s lab expanded E.coli in the presence of physiologically relevant concentrations of five commonly prescribed antidepressants for 60 days and measured the growth of bacteria on agar plates infused with different antibiotics. They looked at antibiotics with different mechanisms of action: some that worked by inhibiting DNA synthesis in bacteria, some that worked by inhibiting protein synthesis, and some that worked by inhibiting cell wall synthesis. . They found that the antidepressants they tested induced resistance to multiple antibiotics in one day.
This group did a ton of experiments to try to figure out how this happened, starting with sequencing the DNA, mRNA and proteins of antibiotic-resistant bacteria. They found that antidepressants cause bacteria to produce reactive oxygen species, which can damage cellular components. This appeared to be essential for the evolution of antibiotic resistance, since resistance did not occur when cells were cultured without oxygen. The drugs also caused the bacteria to express more efflux pump proteins that divert antibiotics from the cell. Genetic mutations in bacterial chromosomes that promoted multi-drug resistance were also more common.
The scientists then looked at time-lapse microscopy images of DNA moving between bacterial cells, a process that may enable the rapid spread of resistance genes. Guess what? SSRI accelerated it and increased its occurrence, allowing resistant bacteria to spread resistance horizontally to their peers (in addition to vertically to their offspring).
Perseverance can lead to resistance
Antidepressants also increased the percentage of bacterial cells that persisted in the presence of high concentrations of antibiotics. These “persistents” aren’t quite antibiotic resistant, exactly – they don’t have any of the genetic mutations that confer antibiotic resistance. They are still normal bacteria; they just randomly have a higher tolerance to antibiotics than their peers. The researchers generated a mathematical model of bacterial evolution, which suggests that antidepressants increase the rate at which normal, persistent bacteria evolve into fully-fledged multidrug-resistant strains.
Antibiotic resistance is a huge threat to human health. Since antidepressants are prescribed and used in such large quantities, the fact that they can induce antibiotic resistance should not be considered one of their more innocuous side effects. It could even be taken into account in the design of new, more effective antidepressants.
PNAS2023. DOI: 10.1073/pnas.2208344120
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