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Objectives: The various sequence types (STs) of Pseudomonas aeruginosa (P. aeruginosa) high-risk clones (HiRiCs) have been sporadically reported in China, but the systematic analysis of genomes for these STs remains limited. This study aimed to address the evolutionary pathways underlying the emergence of HiRiCs and their routes of dissemination from Chinese and global perspectives. Methods: The phylogenetic analysis was performed based on 416 newly sequenced clinical P. aeruginosa strains from Guangdong (GD), published genome sequences of 282 Chinese isolates, and 868 HiRiCs isolates from other countries. The genomic comparison study of global HiRiC ST244 was conducted to detect the model of global dissemination and local separation driven by association regional-specific antibiotic resistance genes. Furthermore, the evolutionary route of the emerging, China-specific HiRiC ST1971 was explored using Most Recent Common Ancestor (MRCA) analysis. Results: Based on comparative genomics analysis, we found a clear geographical separation of ST244 isolates, yet with a association between ST244 isolates from GD and America. We identified a set of 38 AMR genes that contribute to the geographical separation in ST244, and identify genetic determinants either positively (MexB) and negatively (opmD) associated with GD ST244. For the China-unique HiRiC ST1971, its evolutionary history across different continents before emerging as ST1971 in China was also deduced. Conclusion: This study provides insight into the specific genetics underlying regional differences among globally disseminated P. aeruginosa HiRiCs (ST244) as well as new understanding of the dissemination and evolution of a regional HiRiC (ST1971). Understanding the genetics of these and other HiRiCs may assist in controlling their emergence and further spread.

The ever-increasing prevalence of infections produced by multidrug-resistant or extensively drug-resistant Pseudomonas aeruginosa is commonly linked to a limited number of aptly-named epidemical 'high-risk clones' that are widespread among and within hospitals worldwide. The emergence of new potential high-risk clone strains in hospitals highlights the need to better and further understand the underlying genetic mechanisms for their emergence and success. P. aeruginosa related high-risk clones have been sporadically found in China, their genome sequences have rarely been described. Therefore, the large-scale sequencing of multidrug-resistance high-risk clone strains will help us to understand the emergence and transmission of antibiotic resistances in P. aeruginosa high-risk clones. In this study, 212 P. aeruginosa strains were isolated from 2 tertiary hospitals within 3 years (2018-2020) in Guangdong Province, China. Whole-genome sequencing, multi-locus sequence typing (MLST) and antimicrobial susceptibility testing were applied to analyze the genomic epidemiology of P. aeruginosa in this region. We found that up to 130 (61.32%) of the isolates were shown to be multidrug resistant, and 196 (92.45%) isolates were Carbapenem-Resistant Pseudomonas aeruginosa. MLST analysis demonstrated high diversity of sequence types, and 18 reported international high-risk clones were identified. Furthermore, we discovered the co-presence of exoU and exoS genes in 5 collected strains. This study enhances insight into the regional research of molecular epidemiology and antimicrobial resistance of P. aeruginosa in China. The high diversity of clone types and regional genome characteristics can serve as a theoretical reference for public health policies and help guide measures for the prevention and control of P. aeruginosa resistance.