Abstract

Wastewater is a key reservoir and transmission route for antibiotic resistance genes (ARGs), enabling their spread from influent to effluent and into receiving environments. However, how combined selective pressures (antibiotics, biocides, heavy metals, pharmaceuticals) influence resistant bacteria and ARG persistence over space and time remains poorly understood. Likewise, the role of the wastewater microbiome in ARG dynamics is still unclear, as few studies integrate microbiome shifts with chemical and environmental drivers. Here, we investigated how microbiome dynamics, chemical exposures, and environmental conditions shape clinically relevant ARG dynamics from sewage to receiving environments in Guadeloupe, French Caribbean. We analysed data collected from three wastewater continuums, (hospital-based, domestic, touristic) over four campaigns (September 2021-February 2023). We characterised ARG and microbiome composition spatiotemporal patterns and used a mixed-effect model to investigate ARG associations with potential drivers, including exposome factors, microbiome dissimilarity and environmental factors. Several ARGs were negatively associated with microbiome dissimilarity (Bray-Curtis distances) (aac(6)-Ib, aph(3)-III, blaSHV, blaTEM, intI1, qnrS, sul1 and tetM). Negative associations were also observed between upstream-downstream differences in anti-inflammatory drug concentrations and the abundance of aac(6)-Ib, aph(3)-III, blaCTX-M, ermB, intI1, and tetM. In contrast, ARG relative abundance was positively associated with upstream-downstream differences in antibiotic concentrations, suggesting selection along the continuum. These findings indicate that ARG dissemination along wastewater-to-coastal pathways is shaped by opposing processes, with microbiome turnover potentially limiting ARG persistence while chemical gradients promote specific gene enrichment. The outcome is ARG-specific, with implications for antimicrobial resistance risks associated with recreational waters, seafood consumption, and coastal ecosystem interactions.