Crystal structure of New Delhi metallo-β-lactamase reveals molecular basis for antibiotic resistance

Authors

  • Dustin King,

    1. Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
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  • Natalie Strynadka

    Corresponding author
    1. Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
    • Centre for Blood Research, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
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Abstract

β-Lactams are the most commonly prescribed class of antibiotics and have had an enormous impact on human health. Thus, it is disquieting that an enzyme called New Delhi metallo-β-lactamase-1 (NDM-1) can confer Enterobacteriaceae with nearly complete resistance to all β-lactam antibiotics including the carbapenams. We have determined the crystal structure of Klebsiella pneumoniae apo-NDM-1 to 2.1-Å resolution. From the structure, we see that NDM-1 has an expansive active site with a unique electrostatic profile, which we propose leads to a broader substrate specificity. In addition, NDM-1 undergoes important conformational changes upon substrate binding. These changes have not been previously observed in metallo-β-lactamase enzymes and may have a direct influence on substrate recognition and catalysis.

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