The antiparasitics ivermectin and moxidectin trigger genomic and transcriptomic adaptation in bacteria

The macrocyclic lactone anthelmintics ivermectin and moxidectin are widely used for parasite control and show antibacterial activity in vitro. Given their structural relatedness to macrolide antibiotics, their broad use raises concerns about macrolide cross-resistance and altered bacterial physiology, yet the impact on gut bacterial isolates and underlying mechanisms remains poorly defined. Here, we combined Oxford Nanopore whole genome sequencing with Illumina RNA sequencing across six bacterial isolates analyzed as unexposed controls and as derivatives repeatedly exposed to ivermectin or moxidectin to identify genomic and transcriptomic signatures associated with exposure to these drugs. High-quality genome assemblies enabled integrated analyses across species with distinct cellular architectures and antimicrobial resistance gene arsenals. Across the panel, exposure was associated with i) widespread modulation of ribosome-linked genes and pathways, the molecular target of macrolide antibiotics; ii) context-dependent tuning of pre-existing antimicrobial resistance gene arsenals, such as macB and mdlB; and iii) recurrent alterations in potassium transport systems (ktrA and trkA). These findings suggest that repeated ivermectin or moxidectin exposure can reshape bacterial physiology in ways that may, in specific genetic backgrounds, co-modulate resistance-associated traits.