Abstract
Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely used antibiotic class, the β-lactams, including the most recent generation of carbapenems. Interspecies spread renders these enzymes a serious clinical threat, and there are no clinically available inhibitors. We present the crystal structures of IMP-13, a structurally uncharacterized MBL from the Gram-negative bacterium Pseudomonas aeruginosa found in clinical outbreaks globally, and characterize the binding using solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. The crystal structures of apo IMP-13 and IMP-13 bound to four clinically relevant carbapenem antibiotics (doripenem, ertapenem, imipenem, and meropenem) are presented. Active-site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.
Highlights
Multidrug resistance among Gram-negative bacteria is a major global public health threat
While much pharmaceutical research has focused on drugs to treat Gram-positive bacterial infections, multidrug resistance among Gram-negative pathogens remains a significant clinical challenge [1,2,3]. -Lactam antibiotics are used for the treatment of both Gram-negative and Gram-positive bacterial infections and are the most commonly prescribed antibiotics [4, 5]. -Lactam antibiotics act as inhibitors of cell wall biosynthesis, causing subsequent bacterial cell death [6]
Resistance mechanisms can be divided into mutation of penicillin binding proteins (PBPs), which prevent the binding of -lactams to their target protein; reduction of the antibiotic concentration in the cell due to increased
Summary
Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo--lactamases (MBLs) target the most widely used antibiotic class, the -lactams, including the most recent generation of carbapenems. Interspecies spread renders these enzymes a serious clinical threat, and there are no clinically available inhibitors. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo--lactamase inhibitors, essential in the fight against antibiotic resistance. -lactamases that are capable of inactivating the most recent generation of carbapenems, often used as a last resort for the effective treatment of infections caused by multidrug-resistant bacteria, have evolved [15] and spread rapidly [16]. Carbapenem resistance is a hallmark of all three of the World Health Organization’s highest-priority pathogens [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
