Structure of Apo- and Monometalated Forms of NDM-1-A Highly Potent Carbapenem-Hydrolyzing Metallo-β-Lactamase

The New Delhi Metallo-beta-lactamase (NDM-1) gene makes multiple pathogenic microorganisms resistant to all known beta-lactam antibiotics. The rapid emergence of NDM-1 has been linked to mobile plasmids that move between different strains resulting in world-wide dissemination. Biochemical studies revealed that NDM-1 is capable of efficiently hydrolyzing a wide range of beta-lactams, including many carbapenems considered as last resort antibiotics. The crystal structures of metal-free apo- and monozinc forms of NDM-1 presented here revealed an enlarged and flexible active site of class B1 metallo-beta-lactamase. This site is capable of accommodating many beta-lactam substrates by having many of the catalytic residues on flexible loops, which explains the observed extended spectrum activity of this zinc dependent beta-lactamase. Indeed, five loops contribute keg residues in the active site including side chains involved in metal binding. Loop 1 in particular, shows conformational flexibility, apparently related to the acceptance and positioning of substrates for cleavage by a zinc-activated water molecule.