Emergence of Dual-Risk Klebsiella pneumoniae: Global Hotspots of Convergence Between Resistance and Hypervirulence

Abstract

BackgroundKlebsiella pneumoniae is a major pathogen causing both healthcare- and community-associated infections. Traditionally classified as classical (cKp) or hypervirulent (hvKp), recent reports suggest increasing overlap between antimicrobial resistance (AMR) and virulence, leading to "dual-risk" clones that are both invasive and difficult to treat. ObjectivesTo perform a large-scale genomic analysis of K. pneumoniae isolates and systematically characterize the convergence of AMR and hypervirulence, with a focus on global distribution, clonal structure, and accessory genome functions. MethodsWe analyzed 3,443 genomes curated from 25 international studies. Virulence scoring was standardized using a Kleborate-based framework, while AMR genes were identified with ResFinder. Multilocus sequence typing (MLST), plasmid replicon typing, and K/O antigen profiling were conducted. Convergence was defined as hvKp (virulence score [≥]3) carrying high-priority AMR determinants. Pan-genome-wide association (pan-GWAS) was performed with Roary and Scoary, followed by functional enrichment using ShinyGO. ResultsAmong hvKp isolates, 59.4% carried carbapenemases, ESBLs, or 16S rRNA methyltransferases, demonstrating widespread convergence. Convergent lineages were dominated by ST231 and ST23, with India and the Middle East identified as geographic hotspots. HvKp isolates carried a higher plasmid replicon burden and were enriched in KL1/KL2 and O1/O2 serotypes. Pan-GWAS revealed hvKp-associated accessory genes linked to envelope stress response, nucleotide metabolism, and membrane transport, highlighting adaptive traits beyond canonical virulence loci. ConclusionOur findings redefine the hvKp/cKp dichotomy as a continuum shaped by plasmids and selective pressures. The emergence of dual-risk clones has urgent implications for diagnostics, surveillance, and treatment strategies in regions with high AMR prevalence.