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.
Highlights
Introduction βLactamases are bacterial enzymes that hydrolytically inactivate β-lactam antibiotics and are a major cause of the emergence of pathogenic bacteria resistant to β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems
The main structural features of MBLs compared with serine-dependent carbapenemases are the presence of a zinc ion, the absence of covalent acyl-enzyme intermediate, and the widen active-site cleft
These characteristics could result in easier access of the long R2 side chain of carbapenem, more effective coordination of the water molecule, and fast breakdown of the tetrahedral intermediate through protonation of the nitrogen of the cleaved β-lactam ring, which may be the reason that all MBLs can hydrolyze carbapenems
Summary
A phylogenetic analysis of class A carbapenemases together with 62 representative class A β-lactamases showed that carbapenemases form six distantly related branches: IMI/NMC-A enzymes, SME enzymes, GES enzymes, KPC enzymes, SFC-1, and SHV-38 [14]. The SME enzymes (Serratia marcescens enzymes), SME-1 to SME-5, have been found exclusively in S. marcescens and the five variants differ from each other by one to three amino acid substitutions. They are chromosomally encoded [24] and have been recovered sporadically throughout USA and Canada [24,25,26]. The GES (Guiana extended-spectrum β-lactamase) family enzymes include 26 variants [27] and differ from each other by one to four amino acid substitutions [28]. SHV-38 was identified from K. pneumoniae and differs by a single substitution from the non-carbapenemase of class A, SHV-1 [35]
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