New Delhi Metallo-β-Lactamase: Structural Insights into β-Lactam Recognition and Inhibition

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.