<p><b>Abstract</b> </p><p>The globally disseminated high-risk CRKP clone ST5422, though frequently harboring multiple carbapenemase genes, exhibits only sporadic occurrence in China. We report a Shanghai genetic clustering involving seven ST5422 CRKP isolates harboring <i>bla</i>_KPC-2. Comprehensive characterization through antimicrobial susceptibility testing, whole-genome sequencing, phylogenetic reconstruction, and virulence/fitness assessments revealed all strains co-harbored <i>bla</i>_CTX-M-15 with homogeneous resistance profiles: high-level resistance to carbapenems, ceftazidime/avibactam, and tigecycline, while maintaining susceptibility to colistin and amikacin. Phylogenetic analysis of all 13 ST5422 strains available in NCBI resolved three distinct clades. Subsequent characterization revealed that our clinical isolates exhibited significantly enhanced virulence and antimicrobial resistance relative to these reference strains. ST5422 isolates showed a higher virulence and certain adaptability compared with NUTH-K2044 and HS11286 (ST11). We conclude that localized dissemination of ST5422 CRKP carrying <i>bla</i>_KPC-2 in China constitutes a significant public health concern requiring coordinated containment strategies. </p><p><b>Importance</b> </p><p><i>K. pneumoniae</i> is one of the most relevant opportunistic pathogens and causes various human infections. CRKP is not only known for its resistance to various antibiotics but also for the emergence of highly virulent strains. ST11 CRKP is the dominant clone, accounting for 60% of CRKP infections in China, while ST5422 is a single locus variant of ST11. A clear understanding of the evolutionary trajectory of this clone is imperative for the formulation of effective containment strategies. The significance of our research is that the seven KPC-2-producing ST5422 isolates exhibited high-level resistance to carbapenems, tigecycline, and ceftazidime-avibactam, and certain adaptability to the environment, phylogenetically closest to China.</p>