Accessory Genomes Drive Independent Spread of Carbapenem-Resistant Klebsiella pneumoniae Clonal Groups 258 and 307

Abstract

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKp) are urgent public health threats. Worldwide dissemination of CRKp has been largely attributed to the clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, Texas is the first large city in the US with co-circulation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. Methods: CRKp isolates were collected as part of the prospective, Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CRKp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis were performed on all CRKp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. An inverse-probability weighted Desirability of Ordinal Outcome Ranking (DOOR) analysis was conducted to determine if patients infected/colonized with CG307 had differences in overall clinical outcomes from patients infected/colonized with CG258. Results: Dissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements harboring carbapenemases, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates contained a diverse repertoire of mobile genetic elements harboring carbapenemases and clustered distinctly from other global CG307 isolates. CG307 were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum beta-lactamases. The DOOR probability estimate (64%; 95% CI: 48, 79) of our Houston-based cohort suggested that there was a general trend for patients infected/colonized with CG307 to have more favorable outcomes than patients infected/colonized with CG258. Conclusions: Our findings suggest parallel co-circulation of high-risk lineages with potentially divergent evolution. CG307 is widely circulating CRKp clone in the Houston region with the potential to transfer major resistance determinants to other non-CG258 CRKp lineages. Our findings provide major insights into the mechanism of epidemic spread of CRKp.