Global population genomics reveals the expansion of a chromosomally stabilized multidrug-resistant subclade of Clostridium perfringens

Clostridium perfringens is a key intestinal pathogen threatening human and animal health globally, yet its genomic diversity, antimicrobial resistance (AMR) evolution, and transmission remain incompletely understood. Here, we conducted a comprehensive genomic analysis of over 4,000 C. perfringens isolates collected worldwide over the past eight decades. We found that the AMR burden has significantly increased over time, and the distribution of AMR genes and their associated mobile genetic elements shows a clear host-related pattern. Phylogeographic analysis indicates that in China, Jilin and Hebei provinces may be the main transmission centers, promoting regional and inter-provincial transmission along livestock movement routes. Notably, we identified the emergence and expansion of a multi-antibiotics resistant clade 4.2 lineage, which gathered a diverse array of resistance determinants and mobile genetic elements in its chromosome through a serial of horizontal genetic transfers. This study establishes a global evolutionary framework and informs One Health surveillance and control of C. perfringens .