Antidepressants can induce mutation and enhance persistence toward multiple antibiotics

Significance

Antibiotic resistance is a global threat to public health and associated with the overuse of antibiotics. Although non-antibiotic drugs occupy 95% of the drug market, their impact on the emergence and spread of antibiotic resistance remains unclear. Here we demonstrate that antidepressants, one of the most frequently prescribed drugs, can induce antibiotic resistance and persistence. Such effects are associated with increased reactive oxygen species, enhanced stress signature responses, and stimulation of efflux pump expression. Mathematical modeling also supported a role for antidepressants in the occurrence of antibiotic-resistant mutants and persister cells. Considering the high consumption of antidepressants (16,850 kg annually in the United States alone), our findings highlight the need to re-evaluate the antibiotic-like side effects of antidepressants.

Abstract

Antibiotic resistance is an urgent threat to global health. Antidepressants are consumed in large quantities, with a similar pharmaceutical market share (4.8%) to antibiotics (5%). While antibiotics are acknowledged as the major driver of increasing antibiotic resistance, little attention is paid to the contribution of antidepressants in this process. Here, we demonstrate that antidepressants at clinically relevant concentrations induce resistance to multiple antibiotics, even following short periods of exposure. Antibiotic persistence was also enhanced. Phenotypic and genotypic analyses revealed the enhanced production of reactive oxygen species following exposure to antidepressants was directly associated with increased resistance. An enhanced stress signature response and stimulation of efflux pump expression were also associated with increased resistance and persistence. Mathematical modeling also predicted that antidepressants would accelerate the emergence of antibiotic-resistant bacteria, and persister cells would help to maintain the resistance. Overall, our findings highlight the antibiotic resistance risk caused by antidepressants.