Geographic containment and virulence-resistance trade-offs drive the evolution of hypervirulent Klebsiella pneumoniae

Abstract

The emergence of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hvCRKP) represents an alarming convergence of enhanced virulence and extensive drug resistance. Here, we present a comprehensive genomic analysis of 2563 clonal complex 23 (CC23) isolates from 62 countries spanning 1932–2024. Our findings reveal that CC23-K1, the dominant hypervirulent sublineage, emerged approximately 170 years ago and diversified into seven major clades with distinct regional dominance. We observe that carbapenem resistance in CC23-K1 exhibits notable instability, with at least 130 independent acquisitions and 20 losses of resistance genes, suggesting an evolutionary trade-off between hypervirulence and antimicrobial resistance. Experimental validation demonstrates that capsule production physically impedes plasmid conjugation, while isolates carrying blaKPC-2, blaNDM-1, or blaNDM-5 frequently exhibit substantial deletion of virulence determinants. Conversely, blaOXA-48-carrying isolates maintain virulence gene integrity, potentially due to their lower hydrolytic activity and reduced fitness costs. The geographic distribution of these resistance mechanisms correlates with regional antimicrobial usage patterns, with European countries with moderate carbapenem use favoring blaOXA-48 in CC23, while Asian countries with higher consumption show patterns favoring high-efficiency carbapenemases incompatible with complete virulence determinants. We also identified core genomic regions with significantly higher mutation rates in resistant isolates, particularly affecting pathways involved in oxidative phosphorylation and reactive oxygen species production. These findings provide additional insights into CC23 evolution and geographical spread, complementing existing knowledge of carbapenemase distribution patterns observed across K. pneumoniae lineages. Graphical abstract: [Figure not available: see fulltext.]