Structural Basis for Carbapenem-Hydrolyzing Mechanisms of Carbapenemases Conferring Antibiotic Resistance

Abstract

Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern. Carbapenemases are the most versatile family of β-lactamases that are able to hydrolyze carbapenems and many other β-lactams. According to the dependency of divalent cations for enzyme activation, carbapenemases can be divided into metallo-carbapenemases (zinc-dependent class B) and non-metallo-carbapenemases (zinc-independent classes A, C, and D). Many studies have provided various carbapenemase structures. Here we present a comprehensive and systematic review of three-dimensional structures of carbapenemase-carbapenem complexes as well as those of carbapenemases. We update recent studies in understanding the enzymatic mechanism of each class of carbapenemase, and summarize structural insights about regions and residues that are important in acquiring the carbapenemase activity.

Acinetobacter baumannii: biology and drug resistance — role of carbapenemases

“…Based on the participation of divalent cations in enzyme activation, carbapenemases can be segregated into metallo-carbapenemases (class B) and non-metallo-carbapenemases (class A, C and D) [65]. Both groups of enzymes comprise the resistance to carbapenems by breaking the amide bond of the beta-lactam ring, however the mechanism of this process differs substantially.…”

“…In the first step, a conserved serine located in the active site of enzymes, attacks the beta-lactam amide bond, assembling an acyl-enzyme complex. This intermediate is hydrolysed afterwards by a deacylating water molecule, forming the hydrolysed product that is released from the active site of the enzyme [65]. It is considered that carbapenem hydrolysing class D beta-lactamases (CHDL) are the most common factor of carbapenem resistance in A. baumannii strains.…”

“…The hydrolysis of carbapenems mediated by metalloenzymes involves a water molecule, which is coordinated to a divalent cation (zinc) in order to activate and disrupt the beta-lactam ring. It is worth emphasizing that metallo-beta-lactamases do not form the covalent acyl-enzyme intermediate [65,66].…”

A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation

“…The classical mechanism of the serine carbapenemases proceeds through a two‐step pathway involving the formation of an acyl‐enzyme intermediate, which is then hydrolyzed by a nucleophilic water molecule 3. All clinically used carbapenem antibiotics have a 6‐hydroxyethyl side chain, the presence of which is proposed to disrupt the hydrolysis step 4, 5, 6.…”

Toxicity of β-Lactam Antibiotics: Pathophysiology, Molecular Biology and Possible Recovery Strategies

“…The IMI and NMC-A enzymes have been found in clinical isolates of Enterobacter cloacae from the United States, Croatia, Finland and France. Most bla IMI−1 genes are located on chromosome and it is related to imi-R gene that limits their dissemination and their expression at a high level [51]. NMC-A and IMI-1 have 97% amino acid similarity and they are similar to the SME-1, with approximately 70% of amino acid identity encoded by bacterial genome B [52].…”