Comprehensive plasmidomic analysis of Helicobacter pylori reveals the potential role of plasmids in pathogenic adaptation and a novel putative toxin-antitoxin system.

Helicobacter pylori is a significant human pathogen associated with gastric diseases, yet the contribution of plasmids to its pathogenicity remains largely unexplored. In this study, we combined plasmid network analysis, dereplication, functional annotation, and phylogenetic approaches to provide a comprehensive genomic and functional characterization of the H. pylori plasmidome using publicly available plasmid sequences. Of 322 plasmids analyzed, we identified 158 high-confidence plasmid sequences, representing 76 non-redundant plasmids (NR-plasmids). Notably, several sequences previously annotated as plasmids were reclassified as Integrative and Conjugative Elements. NR-plasmids were enriched in genes encoding Filamentation induced by cAMP (Fic) family proteins, which clustered into two distinct phylogenetic groups. Conserved motif analysis suggests that these two Fic protein types may form a novel toxin-antitoxin (TA) system, with Type-2 proteins potentially suppressing Type-1 activity, analogous to the TA mechanism described in Campylobacter fetus subsp. venerealis. Additionally, we identified genes encoding ATP-binding cassette (ABC) and major facilitator superfamily efflux pumps, as well as the virulence-associated protein D (VapD), which may contribute to antimicrobial resistance and host colonization, respectively. Our findings reveal the genomic and functional diversity of the H. pylori plasmidome and highlight the need for experimental validation to clarify its role in pathogenicity, antimicrobial resistance, and bacterial adaptation.