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

ABSTRACT: 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

ORGANISM(S): Escherichia coli str. K-12 substr. MG1655

PROVIDER: GSE309890 | GEO | 2026/02/01

REPOSITORIES: GEO