An omics-based framework for investigating the emerging antibiotic resistance gene: The case of estT

The escalating prevalence of antimicrobial resistance (AMR) constitutes a global public health crisis. This is exacerbated by the continuous emergence of new variants and the discovery of previously unrecognized antibiotic resistance genes (ARGs). While advanced AMR surveillance efforts include time-consuming epidemiological investigations and retrospective analyses, critical gaps often remain towards our understanding of the sources of newly identified ARGs. Here, we established a framework integrating omics-based epidemiological investigations, genomic feature analysis of ARGs-carrying bacteria and evolution analysis of novel ARGs. We took the novel resistance gene estT as an example and analyzed it following this framework. Our study revealed that the estT gene was widely prevalent, capable of cross-phyla transmission, and predominantly present in human- and animal-derived bacteria. We explored the genomic characteristics of estT-positive Escherichia coli, Bacillus spp., Mannheimia haemolytica, and Riemerella anatipestifer, uncovering their public health risks. Evolution analysis of estT homologs found historical connections between estTs and tet(X)s. This study provides a systematic strategy for the proactive surveillance of emerging ARGs, enabling omics-data-driven monitoring of ARG evolution and dissemination to mitigate the escalating crisis of AMR.