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Category: Bacterial Pathogenesis
β-Lactams, Penicillin-Binding Proteins, and β-Lactamases, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap07-1.gif /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap07-2.gifAbstract:
Several properties shared by some of the β-lactam antibiotics are spectral characteristics of the β-lactam group; however, in other cases the properties are very different, and it is difficult to give a clear picture of properties of the individual members and how they differ from each other. Penicillin-binding protein (PBPs) are a group of bacterial membrane-bound enzymes whose active sites are available in the periplasmic space. The production of β-lactamases is considered to be the most common mechanism of bacterial resistance to β-lactam antibiotics. According to Ambler, β-lactamases are also grouped into four molecular classes based on their primary sequence homology. Serine β-lactamases differ from serine DD-transpeptidases in that they catalyze the deacylation step very efficiently only with β-lactams that have an aromatic (planar) substituent joined to the secondary amide side chain. The amino acid alignments reveal several conserved boxes that consist of strict identities or homologous amino acids. The significance of the homologies and differences is highlighted by the recent results of X-ray crystallography and site-directed mutagenesis experiments that have demonstrated the three-dimensional structural similarities between representatives of β-lactamases enzymes. Structural studies suggested that the conserved residue Tyr150 is the catalytic base that activates the hydrolytic water for its attack on the acyl intermediate.
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Structures of representative classical and nonclassical β-lactam antibiotics.
Structures of representative classical and nonclassical β-lactam antibiotics.
Basic skeleton and nomenclature systems of penicillins.
Basic skeleton and nomenclature systems of penicillins.
Conformation of the sodium salt of benzylpenicillin in the solid state. R is –NHCOCH2C6H5. The absolute configuration of chiral centers and the α and β positions below or above the plane are shown.
Conformation of the sodium salt of benzylpenicillin in the solid state. R is –NHCOCH2C6H5. The absolute configuration of chiral centers and the α and β positions below or above the plane are shown.
Chemical structure of 6-β-aminopenicillanic acid in its nonionized and zwitterionic forms.
Chemical structure of 6-β-aminopenicillanic acid in its nonionized and zwitterionic forms.
(a to c) Basic skeleton of cephalosporins and cephamycins (a), carbapenems (b), and clavulanic acid (c). (d and e) Chemical structures of cephalosporanic acid (d) and desacetylcephalosporanic acid (e).
(a to c) Basic skeleton of cephalosporins and cephamycins (a), carbapenems (b), and clavulanic acid (c). (d and e) Chemical structures of cephalosporanic acid (d) and desacetylcephalosporanic acid (e).
Resonance in secondary amides, unstrained monocyclic β-lactams, and strained β-lactams.
Resonance in secondary amides, unstrained monocyclic β-lactams, and strained β-lactams.
Hydrogen atoms in penicillins and cephalosporins and coupling signals in the 1H NMR spectra.
Hydrogen atoms in penicillins and cephalosporins and coupling signals in the 1H NMR spectra.
Penicillanic acid derivative structure showing some positions where chemical transformations are made. Chemical mapping of the different positions and orientation of the molecule is very useful for structure-activity relationships.
Penicillanic acid derivative structure showing some positions where chemical transformations are made. Chemical mapping of the different positions and orientation of the molecule is very useful for structure-activity relationships.
Carboxypeptidase and transpeptidase reactions (pathways I and II). These reactions are catalyzed by bacterial PBPs. Pathway III shows the action of a penicillin. The penicilloyl-transpeptidase is more stable than the acyl-d-alanyl-transpeptidase, and consequently the transfer of the acyl group to an amino group does not take place (pathway III).
Carboxypeptidase and transpeptidase reactions (pathways I and II). These reactions are catalyzed by bacterial PBPs. Pathway III shows the action of a penicillin. The penicilloyl-transpeptidase is more stable than the acyl-d-alanyl-transpeptidase, and consequently the transfer of the acyl group to an amino group does not take place (pathway III).
Dreiding stereomodels of penicillin and of the acyl-d-alanyl-d-alanine end of the nascent peptidoglycan. Arrows indicate the position of the OC—N bond in the β-lactam ring of the penicillin and of the OC—N peptide bond joining the two d-alanine residues. Reprinted from D. J. Tipper and J. L. Strominger, Proc. Natl. Acad. Sci. USA 54:1133, 1965, with permission from the publisher.
Dreiding stereomodels of penicillin and of the acyl-d-alanyl-d-alanine end of the nascent peptidoglycan. Arrows indicate the position of the OC—N bond in the β-lactam ring of the penicillin and of the OC—N peptide bond joining the two d-alanine residues. Reprinted from D. J. Tipper and J. L. Strominger, Proc. Natl. Acad. Sci. USA 54:1133, 1965, with permission from the publisher.
Opening of the β-lactam ring by catalysis with a β-lactamase enzyme.
Opening of the β-lactam ring by catalysis with a β-lactamase enzyme.
Inactivation of penicillin by active-site serine β-lactamases.
Inactivation of penicillin by active-site serine β-lactamases.
The penicillin-interactive, serine-active-site PBPs and β-lactamases. Enz, enzyme; C, antibiotic; Enz-C, noncovalent Michaelis complex; Enz-C*, covalent acyl-enzyme; P, inactive degradation product(s) of the antibiotic.
The penicillin-interactive, serine-active-site PBPs and β-lactamases. Enz, enzyme; C, antibiotic; Enz-C, noncovalent Michaelis complex; Enz-C*, covalent acyl-enzyme; P, inactive degradation product(s) of the antibiotic.
Schematic drawing of a possible catalytic mechanism for class A β-lactamases. Through an electrostatic interaction between the ammonium group of Lys234 and the C-3 carboxylate the substrate is recognized by the enzyme in both ground-state binding and transition-state binding. Reprinted from H. Adachi, T. Ohta, and H. Matsuzawa, J. Biol. Chem. 266:3186–3191, 1991, with permission from the publisher.
Schematic drawing of a possible catalytic mechanism for class A β-lactamases. Through an electrostatic interaction between the ammonium group of Lys234 and the C-3 carboxylate the substrate is recognized by the enzyme in both ground-state binding and transition-state binding. Reprinted from H. Adachi, T. Ohta, and H. Matsuzawa, J. Biol. Chem. 266:3186–3191, 1991, with permission from the publisher.
Simplified mechanism of β-lactam hydrolysis by group C β-lactamases. Enz, enzyme.
Simplified mechanism of β-lactam hydrolysis by group C β-lactamases. Enz, enzyme.
Proposed catalytic mechanism of benzylpenicillin hydrolysis by the mononuclear metallo-β-lactamase from B. cereus. H, histidine; Asp, aspartate. Adapted from S. Bounaga, A. P. Laws, M. Galleni, and M. I. Page, Biochem. J. 331:703–711, 1998, with permission from the publisher.
Proposed catalytic mechanism of benzylpenicillin hydrolysis by the mononuclear metallo-β-lactamase from B. cereus. H, histidine; Asp, aspartate. Adapted from S. Bounaga, A. P. Laws, M. Galleni, and M. I. Page, Biochem. J. 331:703–711, 1998, with permission from the publisher.
Catalytic mechanism of nitrocefin hydrolysis by the dizinc metallo-β-lactamase from B. fragilis. H, histidine; C, cysteine; Asp, aspartate; Asn, asparaginamide. Adapted from Z. Wang, W. Fast, and S. J. Benkovic, Biochemistry 38:10013–10023, 1999, with permission from the publisher.
Catalytic mechanism of nitrocefin hydrolysis by the dizinc metallo-β-lactamase from B. fragilis. H, histidine; C, cysteine; Asp, aspartate; Asn, asparaginamide. Adapted from Z. Wang, W. Fast, and S. J. Benkovic, Biochemistry 38:10013–10023, 1999, with permission from the publisher.
Properties of the PBPs of E. coli K-12 a
Properties of the PBPs of E. coli K-12 a
β-Lactamase classification a
β-Lactamase classification a