Chromosomal Integration of Huge and Complex blaNDM-Carrying Genetic Elements in Enterobacteriaceae

<jats:p>In this study, a detailed genetic dissection of the huge and complex <jats:italic>bla</jats:italic><jats:sub>NDM</jats:sub>-carrying genetic elements and their related mobile genetic elements was performed in Enterobacteriaceae. An extensive comparison was applied to 12 chromosomal genetic elements, including six sequenced in this study and the other six from GenBank. These 12 genetic elements were divided into five groups: a novel IME Tn<jats:italic>6588</jats:italic>; two related IMEs Tn<jats:italic>6523</jats:italic> (SGI1) and Tn<jats:italic>6589</jats:italic>; four related ICEs Tn<jats:italic>6512</jats:italic> (R391), Tn<jats:italic>6575</jats:italic> (ICE<jats:italic>Pvu</jats:italic>ChnBC22), Tn<jats:italic>6576</jats:italic>, and Tn<jats:italic>6577</jats:italic>; Tn<jats:italic>7</jats:italic> and its derivatives Tn<jats:italic>6726</jats:italic> and 40.7-kb Tn<jats:italic>7</jats:italic>-related element; and two related IMEs Tn<jats:italic>6591</jats:italic> (GI<jats:italic>sul2</jats:italic>) and Tn<jats:italic>6590</jats:italic>. At least 51 resistance genes, involved in resistance to 18 different categories of antibiotics and heavy metals, were found in these 12 genetic elements. Notably, Tn<jats:italic>6576</jats:italic> carried another ICE Tn<jats:italic>6582</jats:italic>. In particular, the six <jats:italic>bla</jats:italic><jats:sub>NDM</jats:sub>-carrying genetic elements Tn<jats:italic>6588</jats:italic>, Tn<jats:italic>6589</jats:italic>, Tn<jats:italic>6575</jats:italic>, Tn<jats:italic>6576</jats:italic>, Tn<jats:italic>6726</jats:italic>, and 40.7-kb Tn<jats:italic>7</jats:italic>-related element contained large accessory multidrug resistance (MDR) regions, each of which had a very complex mosaic structure that comprised intact or residual mobile genetic elements including insertion sequences, unit or composite transposons, integrons, and putative resistance units. Core <jats:italic>bla</jats:italic><jats:sub>NDM</jats:sub> genetic environments manifested as four different Tn<jats:italic>125</jats:italic> derivatives and, notably, two or more copies of relevant Tn<jats:italic>125</jats:italic> derivatives were found in each of Tn<jats:italic>6576</jats:italic>, Tn<jats:italic>6588</jats:italic>, Tn<jats:italic>6589</jats:italic>, and 40.7-kb Tn<jats:italic>7</jats:italic>-related element. The huge and complex <jats:italic>bla</jats:italic><jats:sub>NDM</jats:sub>-carrying genetic elements were assembled from complex transposition and homolog recombination. Firstly identified were eight novel mobile elements, including three ICEs Tn<jats:italic>6576</jats:italic>, Tn<jats:italic>6577</jats:italic>, and Tn<jats:italic>6582</jats:italic>, two IMEs, Tn<jats:italic>6588</jats:italic> and Tn<jats:italic>6589</jats:italic>, two composite transposons Tn<jats:italic>6580a</jats:italic> and Tn<jats:italic>6580b</jats:italic>, and one integron In1718.</jats:p>