New Delhi metallo-beta-lactamase: structural insights into beta-lactam recognition and inhibition.
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King DT, Worrall LJ, Gruninger R, Strynadka NC
New Delhi metallo-beta-lactamase: structural insights into beta-lactam recognition and inhibition.
J Am Chem Soc. 2012 Jul 18;134(28):11362-5. doi: 10.1021/ja303579d. Epub 2012 Jul 5.
- PubMed ID
- 22713171 [ View in PubMed]
- Abstract
The beta-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-beta-lactamase-1 (NDM-1) has been found to confer enteric bacteria resistance to nearly all beta-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-beta-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 A, respectively, and represent the highest-resolution structural data for any metallo-beta-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-beta-lactamases.