Stability-oriented chemical-biological integration prioritizes antimicrobials linked to resistome variation in landfill leachates across China.

Landfill leachate contains complex mixtures of antimicrobials and other stressors, making it difficult to identify chemical signals consistently associated with environmental resistomes. We integrated targeted antimicrobial measurements with metagenomic antibiotic resistance gene (ARG) profiles from landfill leachates collected in 17 Chinese cities across 12 provinces. Among 52 detected antimicrobials, 37 had risk quotients (RQs) > 0.1, 25 exceeded 1, and 12 exceeded 10 in at least one site; 296 ARG subtypes were detected. Pairwise and matrix-level analyses showed fragmented antimicrobial-ARG relationships. Using Shannon diversity as a resistome-level endpoint, a stability-oriented multivariable analysis prioritized clinafloxacin, clindamycin hydrochloride, and sulfathiazole. Their bootstrap recurrence frequencies were 0.752, 0.389, and 0.226, respectively, with the same stability hierarchy supported by alternative selection and site-omission analyses; clinafloxacin was also least sensitive to measured antimicrobial covariance. Covariate-adjusted higher-versus-lower exposure contrasts were -0.467, +0.250, and +0.089 Shannon units, respectively, with sulfathiazole showing greater context dependence. Integrating chemical exposure with resistome responses thus complements conventional occurrence- and RQ-based screening by adding a biological-response layer for prioritizing reproducible antimicrobial signals within complex environmental mixtures.