Molecular evolution and mechanisms underlying extremely high-level carbapenem resistance in the emerging CRPA clone ST1976

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) represents a critical threat to clinical therapy, yet the genetic basis underlying extremely high-level carbapenem resistance remains poorly understood. An emerging CRPA clone, ST1976, has recently been identified in China with unusually high meropenem MICs. ST1976 CRPA isolates collected between 2018 and 2022 were subjected to antimicrobial susceptibility testing, whole-genome and Nanopore sequencing, and bioinformatic analyses. Cloning assays and sodium mercaptoacetic acid inhibition tests were performed to investigate the molecular basis of carbapenem resistance. During the study period from 2018 to 2022, ST1976 was one of the predominant CRPA clones in Henan Province, exhibiting a significantly increasing trend and carrying significantly more resistance and virulence genes than other major regional clones. Phylogenomic analyses suggested that ST1976 emerged approximately two decades ago and may serve as a regional reservoir of blaIMP-10. In this study, the blaIMP-10 gene in all ST1976 CRPA isolates was located on the same plasmid type, and carriage of this plasmid did not impose a significant fitness cost on the bacterial host. Notably, all blaIMP-10-positive ST1976 isolates displayed extremely high-level meropenem resistance (MICs ≥ 1280 µg/mL), primarily mediated by IMP-10, with additional contributions from chromosomal oprD mutations. ST1976 represents an emerging high-risk CRPA clone characterized by convergent plasmid- and chromosome-mediated mechanisms driving extremely high-level carbapenem resistance, highlighting the need for enhanced surveillance and targeted interventions.