An ancient family of mobile genomic islands introducing cephalosporinase and carbapenemase genes in <i>Enterobacteriaceae</i>

<p>The exchange of mobile genomic islands (MGIs) between microorganisms is often mediated by phages, which may provide benefits to the phage’s host. The present study started with the identification of <i>Enterobacter cloacae, Klebsiella pneumoniae</i> and <i>Escherichia coli</i> isolates with exceptional cephalosporin and carbapenem resistance phenotypes from patients in a neonatal ward. To identify possible molecular connections between these isolates and their β-lactam resistance phenotypes, the respective bacterial genome sequences were compared. This unveiled the existence of a family of ancient MGIs that were probably exchanged before the species <i>E. cloacae, K. pneumoniae</i> and <i>E. coli</i> emerged from their common ancestry. A representative MGI from <i>E. cloacae</i> was named MIR17-GI, because it harbors the novel β-lactamase gene variant <i>bla</i><sub>MIR17</sub>. Importantly, our observations show that the MIR17-GI-like MGIs harbor genes associated with high-level resistance to cephalosporins. Among them, MIR17-GI stands out because MIR17 also displays carbapenemase activity. As shown by mass spectrometry, the MIR17 carbapenemase is among the most abundantly expressed proteins of the respective <i>E. cloacae</i> isolate. Further, we show that MIR17-GI-like islands are associated with integrated P4-like prophages. This implicates phages in the spread of cephalosporin and carbapenem resistance amongst <i>Enterobacteriaceae</i>. The discovery of an ancient family of MGIs, mediating the spread of cephalosporinase and carbapenemase genes, is of high clinical relevance, because high-level cephalosporin and carbapenem resistance have serious implications for the treatment of patients with enterobacteriaceal infections.</p>