Global resistome architecture of Escherichia coli across human and animal hosts: analysis of 9,696 genome

Escherichia coli is a ubiquitous bacterium that acts both as a commensal and a pathogen, serving as a major reservoir of antimicrobial resistance genes (ARGs). The global spread of ARGs, particularly those conferring resistance to last-resort antibiotics such as carbapenems and colistin, poses a serious threat to human and animal health. In this study, we analyzed 9,696 publicly available E. coli genomes from human, animal, and unknown-origin metadata, identifying 42,813 acquired ARG occurrences across ten antibiotic classes. Multidrug resistance (ARGs from ≥ 3 classes) was observed in 44.7% of genomes, with aminoglycoside-modifying enzymes, multidrug efflux pumps, and β-lactamases being the most abundant. Clinically important genes, including bla_TEM-1B, bla_CTX-M-15, bla_NDM-5, and mcr-1.1, were widely prevalent across hosts. Using binary presence/absence profiles, co-occurrence analyses revealed structured resistance gene modules, with strong associations among aminoglycoside, sulfonamide, and trimethoprim genes consistent with integron-associated assemblages. In contrast, major β-lactamase genes and efflux determinants showed weaker and more heterogeneous co-occurrence patterns, suggesting frequent independent acquisition. Geographic and host analyses highlighted significant heterogeneity and extensive ARG sharing between humans and animals. This study provides a global-scale overview of the E. coli resistome across human and animal hosts, offering a reference framework for genomic surveillance and informing strategies to curb the spread of multidrug-resistant lineages.