Abstract
Carbapenem-resistant Proteus mirabilis (CRPM), largely driven by dissemination of bla(NDM-1), poses a growing global threat, yet its phylogeographic and genetic patterns remain understudied. We analyzed 16 bla(NDM-1)-harboring CRPM clinical isolates from a tertiary hospital in China (2017-2024) using antimicrobial susceptibility testing, conjugation assays, whole-genome sequencing, and growth experiments. We found that bla(NDM-1) dissemination occurred primarily via plasmids and Salmonella Genomic Island 1 (SGI1), including a novel SGI1-PM16 variant. Early transmission events were associated with Tn125-derived elements (ΔTn125), while ISCR1 appeared to mediate rolling-circle transposition and likely facilitated local amplification of resistance cassettes. Additionally, we performed a global genomic epidemiological study of 420 bla(NDM)-positive CRPM genomes curated from NCBI (accessed 21 April 2025). ST135 emerged as the predominant clone among CRPM in China. Phylogeographic analysis of P. mirabilis worldwide clarified the geographic prevalence of NDM variants. In the United States, bla(NDM-7) predominates, whereas bla(NDM-1) is most frequent in China. In summary, this study provides crucial insights into the resistance mechanisms and transmission dynamics of CRPM, as well as underscores the need to enhance genomic surveillance and optimize infection control strategies to mitigate the spread of bla(NDM-1)-harboring CRPMs. IMPORTANCE: To date, the phylogeographic distribution of bla(NDM)-carrying CRPMs has not been determined. Our study identified ST135 as the predominant bla(NDM)-producing clone, with a distinct global distribution pattern of NDM variants. Furthermore, we elucidated critical bla(NDM-1) transmission mechanisms, revealing both plasmid- and SGI1-mediated dissemination and ISCR1-driven gene amplification, while also characterizing a novel SGI1-PM16 variant. These findings provide significant new insights into the molecular mechanisms underlying acquired antimicrobial resistance.