New Delhi Metallo-β-Lactamase: Structural Insights into β-Lactam Recognition and Inhibition
Citations Over TimeTop 10% of 2012 papers
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 Å, 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.
Related Papers
- → Molecular modeling of γ-lactam analogues of β-lactam antibacterial agents: synthesis and biological evaluation of selected penem and carbapenem analoques(1989)47 cited
- → Structural insights into the γ-lactamase activity and substrate enantioselectivity of an isochorismatase-like hydrolase from Microbacterium hydrocarbonoxydans(2017)12 cited
- → Synthetic Studies on Carbapenem Antibiotics: A Carbon-introduced Reaction at the C-4 Position of a b-Lactam by Carbane Insertion Reaction(1982)28 cited
- → Synthesis of γ-lactam analogues of 1-acetoxy carbapenem derivatives(1990)12 cited
- → ChemInform Abstract: Molecular Modeling of γ‐Lactam Analogues of β‐Lactam Antibacterial Agents: Synthesis and Biological Evaluation of Selected Penem and Carbapenem Analogues.(1989)