Global spread characteristics of CTX-M-type extended-spectrum β-lactamases: A genomic epidemiology analysis

Extended-spectrum β-lactamases (ESBLs) producing bacteria have spread worldwide and become a global public health concern. Plasmid-mediated transfer of ESBLs is an important route for resistance acquisition.

We collected 1345 complete sequences of plasmids containing CTX-Ms from public database. The global transmission pattern of plasmids and evolutionary dynamics of CTX-Ms have been inferred. We applied the pan-genome clustering based on plasmid genomes and evolution analysis to demonstrate the transmission events.

Totally, 48 CTX-Ms genotypes and 186 incompatible types of plasmids were identified. The geographical distribution of CTX-Ms showed significant differences across countries and continents. CTX-M-14 and CTX-M-55 were found to be the dominant genotypes in Asia, while CTX-M-1 played a leading role in Europe. The plasmids can be divided into 12 lineages, some of which forming distinct geographical clusters in Asia and Europe, while others forming hybrid populations. The Inc types of plasmids are lineage-specific, with the CTX-M-1_IncI1-I (Alpha) and CTX-M-65_IncFII (pHN7A8)/R being the dominant patterns of cross-host and cross-regional transmission. The IncI-I (Alpha) plasmids with the highest number, were presumed to form communication groups in Europe-Asia and Asia-America-Oceania, showing the transmission model as global dissemination and regional microevolution. Meanwhile, the main kinetic elements of bla_CTX-Ms showed genotypic preferences. ISEcpl and IS26 were most frequently involved in the transfer of CTX-M-14 and CTX-M-65, respectively. IS15 has become a crucial participant in mediating the dissemination of bla_CTX-Ms. Interestingly, bla_TEM and bla_CTX-Ms often coexisted in the same transposable unit. Furthermore, antibiotic resistance genes associated with aminoglycosides, sulfonamides and cephalosporins showed a relatively high frequency of synergistic effects with CTX-Ms.

We recognized the dominant bla_CTX-Ms and mainstream plasmids of different continents. The results of this study provide support for a more effective response to the risks associated with the evolution of bla_CTX-Ms-bearing plasmids, and lay the foundation for genotype-specific epidemiological surveillance of resistance, which are of important public health implications.