Antidepressant sertraline biases resistance emergence via stress-driven rewiring of the pentose phosphate pathway: tktA enables metabolic rollback

Selective serotonin reuptake inhibitors (SSRIs) may accelerate antibiotic resistance, but the metabolic changes behind this process—and how to restore susceptibility—are still not well understood. We demonstrated that sertraline led to a biased resistance profile in Escherichia coli, characterized by early accumulation of mutations targeting rifampicin and ciprofloxacin. These genetic alterations were linked to a compensatory respiratory mechanism dependent on Complex I, leading to reduced nicotinamide adenine dinucleotide and superoxide/hydrogen peroxide buildup. They also caused a rapid shift of glucose from glycolysis to the pentose-phosphate pathway (PPP) to produce reduced nicotinamide adenine dinucleotide phosphate during oxidative stress, similar to paraquat-like redox stress. Inhibiting the non-oxidative PPP, especially transketolase A (tktA), eliminated the sertraline-primed advantage and brought back antibiotic susceptibility, decreasing survival by approximately 10,000 times during antibiotic challenge, even with rpoBC and gyrAB mutations fixed. These findings uncover an electron transfer chain/PPP–coupled redox module as the hidden driver behind sertraline-induced resistance, highlighting mutation-agnostic ways to restore bacterial sensitivity. By reframing SSRI-induced resistance as a modifiable metabolic trait, we provide a basis for using metabolic adjuvants to shield the millions of SSRI users from the unintended risk of antibiotic resistance—transforming a pharmacological challenge into a manageable, reversible target Overall design: RNA-seq profiling of Escherichia coli MG1655 after 40 days of adaptive evolution under 40 mg/L sertraline to compare differential gene expression.