The transfer of antibiotic resistance genes between evolutionarily distant bacteria.

Infections from antibiotic-resistant bacteria threaten human health globally. Resistance is often caused by mobile antibiotic resistance genes (ARGs) shared horizontally between bacterial genomes. Many ARGs originate from environmental and commensal bacteria and are transferred between divergent bacterial hosts before they reach pathogens. This process remains, however, poorly understood, which complicates the development of countermeasures that reduce the spread of ARGs. In this study, we aimed to systematically analyze the ARGs transferred between the most evolutionarily distant bacteria, defined here based on their phylum. We implemented an algorithm that identified inter-phylum transfers (IPTs) by combining ARG-specific phylogenetic trees with the taxonomy of the bacterial hosts. From the analysis of almost 1 million ARGs identified in >400,000 bacterial genomes, we identified 661 IPTs, which included transfers between all major bacterial phyla. The frequency of IPTs varies substantially between ARG classes and was highest for the aminoglycoside resistance gene AAC(3), while the levels for beta-lactamases were generally lower. ARGs involved in IPTs also differed between phyla, where, for example, tetracycline ARGs were commonly transferred between Firmicutes and Proteobacteria, but rarely between Actinobacteria and Proteobacteria. The results, furthermore, show that conjugative systems are seldom shared between bacterial phyla, suggesting that other mechanisms drive the dissemination of ARGs between divergent hosts. We also show that bacterial genomes involved in IPTs of ARGs are either over- or underrepresented in specific environments. These IPTs were also found to be more recent compared to transfers associated with bacteria isolated from water, soil, and sediment. While macrolide and tetracycline ARGs involved in IPTs almost always were >95% identical between phyla, corresponding β-lactamases showed a median identity of <60%. We conclude that inter-phylum transfer is recurrent, and our results offer new insights into how ARGs are disseminated between evolutionarily distant bacteria. IMPORTANCE: Antibiotic-resistant infections pose a growing threat to global health. This study reveals how genes conferring antibiotic resistance can move between bacteria that belong to different phyla lineages previously thought to be too evolutionarily distant for frequent gene exchange. By analyzing nearly 1 million resistance genes from over 400,000 bacterial genomes, the researchers uncovered hundreds of inter-phylum transfer events, exposing surprising patterns in how different classes of resistance genes spread. The findings highlight that conjugative systems are less common than expected in cross-phyla transfers and suggest that alternative mechanisms may play key roles. This new understanding of how resistance genes leap between vastly different bacterial groups can inform strategies to slow the emergence of drug-resistant infections, aiding in the development of more effective public health interventions.