Promiscuous mobile elements spread antibiotic resistance from the microbiome

Horizontal transfer of mobile genetic elements between bacteria is a primary mechanism for the dissemination of antibiotic resistance genes (ARGs). In the human gastrointestinal microbiome, identification and experimental validation of ARG dissemination networks has been limited by unavailability of purified isolates. Here, we perform isolate level computational and experimental validation of novel mobile elements that are capable of broad-range, inter-phylum transfer between human enteropathogens and gut symbiont species. By analyzing a collection of 1354 high quality draft genome sequences from cultured human gastrointestinal bacterial isolates (540 species) and 45,403 human enteropathogen strains (12 species) we found 81,732 examples of horizontally acquired ARGs. Informatic analysis identified 15 promiscuous mobile genetic elements (0.02%), eight with novel replication genes, that were carried by both symbiont bacteria and enteropathogens from multiple phyla across body sites. Phenotypic analysis and long-read sequencing confirmed the transfer of ARG encoding mobile elements from Dorea longicatena and Clostridium hathewayi to the phylogenetically distant enteropathogen Klebsiella oxytoca. This work identifies and experimentally validates mobility of key broad-range mobile genetic elements found in the human microbiome, ruminant microbiome and environmental sources that represent important targets in managing the spread of antibacterial resistance.