Global Insights into Evolution and Adaptation in KPC and NDM Coproducing Carbapenem-Resistant Klebsiella pneumoniae.

ObjectivesThe worldwide dissemination of carbapenem-resistant Klebsiella pneumoniae co-producing KPC and NDM (KPC-NDM-CRKP) poses a substantial clinical challenge. MethodsThis study characterized 5 KPC-NDM-CRKP isolates from a tertiary hospital in southern China and integrated 460 global isolates genomes to demonstrate the population framework of this epidemic pathogen. Results5 clinical isolates were multidrug resistance, exhibiting high level resistance to first-line drugs including carbapenems and ceftazidime/avibactam. Globally, KPC-2-NDM-1 (50.3%) were the most common and an increasing trend of ST11-KL64 (20%) isolates carrying iucA and rmpA/A2. Resistance and virulence genes were positively associated with specific mobile elements including blaKPC-3 with Tn4401, iucABC with IncHI1B, iroBCDN with IncQ1. The phylogenetic analysis revealed distinct lineage-specific mutations and pan-genome enrichments synergistically promoted adaptive evolution: cluster 1 had membrane transport and secretion but enhanced immune evasion and horizontal gene transfer, cluster 3 adapted metabolically for nutrient-limited niches; cluster 4 reprogrammed metabolism for host adaptation, cluster 6 displayed membrane repair and reduced virulence (e.g., KC187). High-risk iucA/rmpA-positive isolates in cluster 2 acquired enhanced virulence and metabolic adaptive capacity through recombination hotspots (ABC transporters DdpABCD, efflux systems MdtABCD, metabolic enzymes XylB and MtlD, regulators BaeR and OmpR) and pan-genome enrichment (siderophore biosynthesis, toxin-antitoxin VapC and restriction-modification systems). Functionally, these traits correlated with high mucoviscosity, serum resistance, siderophore production and lower survival rates in G. mellonella that contribute to epidemiological success. ConclusionsThese findings demonstrated the discrete mutation, horizontal transfer, and accessory genome plasticity collectively drove the epidemiological success of KPC-NDM-CRKP.