Antibiotic stress response in a medicinal plant: Sulfamethoxazole–mediated regulation of growth and bioactive compound biosynthesis in Isatis indigotica

Antibiotic contamination in soil poses a significant ecological threat, its toxicological effects on medicinal plants remain poorly understood. This study explored the dual effects of sulfamethoxazole (SMX) on Isatis indigotica, a medicinal herb with notable antibacterial and anti-inflammatory properties. SMX exposure induced concentration-dependent phytotoxicity, suppressing root growth and biomass while disrupting the tryptophan biosynthetic pathway and reducing indole-3-acetic acid production. SMX exposure also induced a robust plant defense response, characterized by the upregulation of tryptophan metabolism and the enhanced biosynthesis of secondary metabolites (including indoles, coumarins, phenolics, flavonoids, lignins, and organic acids) with established antioxidant and defensive functionalities. Proteomic profiling of the medicinally relevant root tissue (Radix Isatidis) revealed that medium-to-high SMX downregulated shikimate pathway-derived aromatic amino acids, while the highest SMX selectively upregulated phenylpropanoid biosynthesis, indicating a shift from primary growth to secondary metabolism and a growth-defense trade-off affecting active compound accumulation. Integrated metabolomics-proteomics correlation network analysis further revealed coordinated regulation between key metabolic pathways, highlighting a system-level metabolic reprogramming underlying the growth-defense trade-off under SMX stress. Chemical fingerprinting further confirmed increased accumulation of bioactive constituents at elevated SMX levels. Zebrafish inflammation assays demonstrated reduced pharmacological efficacy under low-to-medium SMX exposure, but enhanced effects at high concentrations. Collectively, these findings elucidate a paradoxical dual impact of soil antibiotic contamination on medicinal plants-the active ingredients may increase under high-concentration exposure, this effect cannot offset negative impact of pollution on plant growth, nutrient accumulation, ecosystem functions. These findings highlight the impact of soil antibiotic pollution on the overall health and environmental safety of medicinal plants.