Emergence and Evolution of Multidrug-Resistant Klebsiella pneumoniae with both blaKPC and blaCTX-M Integrated in Chromosome [PublishAheadOfPrint]

The extended-spectrum β-lactamase (ESBL)- and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae represent serious and urgent threats to public health. In a retrospective study of multidrug-resistant K. pneumoniae, we identified three clinical isolates, CN1, CR14 and NY9, carrying both bla_CTX-M and bla_KPC genes. The complete genomes of these three K. pneumoniae isolates were de novo assembled by using both short- and long-read whole-genome sequencing. In CR14 and NY9, bla_CTX-M and bla_KPC were carried on two different plasmids. In contrast, CN1 had one bla_KPC-2 and three copies of bla_CTX-M-15 integrated in the chromosome, for which the bla_CTX-M-15 genes were linked to an insertion sequence ISEcp1, whereas bla_KPC-2 gene was in the context of a Tn4401a transposition unit conjugated with a PsP3-like prophage. Intriguingly, downstream of the Tn4401a-bla_KPC-2-prophage genomic island, CN1 also carried a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-cas array with four spacers targeting a variety of K. pneumoniae plasmids harboring antimicrobial resistance genes. Comparative genomic analysis revealed that there were two subtypes of Type I-E CRISPR-cas in K. pneumoniae strains; and suggested that the evolving CRISPR-cas with its acquired novel spacer might have induced the mobilization of antimicrobial resistance genes from plasmids into chromosome. The integration and dissemination of multiple copies of bla_CTX-M and bla_KPC from plasmids to chromosome depicts the complex pandemic scenario of multidrug-resistant K. pneumoniae. Additionally, the implications from this study also raise concern for the application of a CRISPR-cas strategy against antimicrobial resistance.

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