Download MendeleyNew Delhi Metallo-Beta-Lactamase: Structural Insights into Beta-Lactam Recognition and Inhibition
King, D.T., Worrall, L.J., Gruninger, R., Strynadka, N.C.(2012) J Am Chem Soc 134: 11362-11365
- PubMed: 22713171
- DOI: https://doi.org/10.1021/ja303579d
- Primary Citation of Related Structures:
4EXS, 4EXY, 4EY2, 4EYB, 4EYF, 4EYL - PubMed Abstract:
The β-lactam antibiotics have long been a cornerstone for the treatment of bacterial disease. Recently, a readily transferable antibiotic resistance factor called the New Delhi metallo-β-lactamase-1 (NDM-1) has been found to confer enteric bacteria resistance to nearly all β-lactams, including the heralded carbapenems, posing a serious threat to human health. The crystal structure of NDM-1 bound to meropenem shows for the first time the molecular details of how carbapenem antibiotics are recognized by dizinc-containing metallo-β-lactamases. Additionally, product complex structures of hydrolyzed benzylpenicillin-, methicillin-, and oxacillin-bound NDM-1 have been solved to 1.8, 1.2, and 1.2 ?, respectively, and represent the highest-resolution structural data for any metallo-β-lactamase reported to date. Finally, we present the crystal structure of NDM-1 bound to the potent competitive inhibitor l-captopril, which reveals a unique binding mechanism. An analysis of the NDM-1 active site in these structures reveals key features important for the informed design of novel inhibitors of NDM-1 and other metallo-β-lactamases.
Organizational Affiliation:
Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
