SHV-Type b-Lactamases. Pp. 847-864.
Leonidas S. Tzouvelekis and Robert A. Bonomo
[Abstract]
OXA-Type b-Lactamases. Pp. 865-879.
Thierry Naas and Patrice Nordmann
[Abstract]
Regulation of Inducible AmpC Beta-Lactamase Expression Among Enterobacteriaceae.
Pp. 881-894.
N.D. Hanson and C.C. Sanders
[Abstract]
The Reactivity of b-Lactams, the Mechanism
of Catalysis and the Inhibition of b-Lactamases.
Pp. 895-913.
Michael I. Page
[Abstract]
Class B b-Lactamases: the Importance of Being
Metallic. Pp. 915-927.
Julia A. Cricco and Alejandro J. Vila
[Abstract]
Structural and Mechanistic Aspects of Evolution of b-Lactamases
and Penicillin-Binding Proteins. Pp. 929-937.
Irina Massova and Shahriar Mobashery
[Abstract]
Recent Advances in the Chemistry of b-Lactam
Compounds as Selected Active-site Serine b-Lactamase
Inhibitors. Pp. 939-953.
Oreste A. Mascaretti, Gerardo O. Danelon, Eduardo L. Setti, María
Laborde and Ernesto G. Mata
[Abstract]
Solid-phase and Combinatorial Synthesis in b-Lactam
Chemistry. Pp. 955-964.
Ernesto G. Mata
[Abstract]
[Back to top] SHV-Type
b-Lactamases.
Leonidas S. Tzouvelekis and Robert A. Bonomo.
The group of plasmid-mediated SHV b-Lactamases
includes SHV-1 and at least twenty-three variants, most of which possess
extended-spectrum (ES) activity against the newer broad-spectrum cephalosporins.
Their likely ancestor is a chromosomal penicillinase of Klebsiella pneumoniae.
SHV enzymes belong to the molecular class A of serine b-Lactamases
and share extensive functional and structural similarity with TEM b-Lactamases.
The three-dimensional structure of the SHV-1 b-Lactamase
possesses an active site wider than that of TEM-1 b-Lactamase
by 0.7 to 1.2 Å. This results in subtle, yet important, differences
in the positioning of critical active-site residues. SHV-1 b-Lactamase
behaves as a typical penicillinase hydrolyzing penicillins and early generation
cephalosporins. SHV-1 b-Lactamase has spread,
via plasmids, to virtually all enterobacterial species but is encountered
mostly in K. pneumoniae. ES SHV b-Lactamases
are found with increasing frequency in K. pneumoniae and other enterobacterial
isolates and are now considered the most prevalent ES b-Lactamases.
These ES SHV b-Lactamases confer a wide spectrum
of resistance to b-Lactams, including the new
generation cephalosporins and monobactams, and are usually encoded by self-transmissible
multi-resistant plasmids that are highly mobile. Extension of the hydrolytic
spectrum of ES SHV enzymes to include oximino-b-Lactams
is seen as a result of substitutions of critical amino acid residues that
alter the properties of the active site. These mutational changes, however,
result in diminished hydrolytic activity against penicillins and an increased
susceptibility to mechanism-based inhibitors. Understanding the substrate
evolution, properties and modes of spread of these clinically important
b-Lactamases
can help in formulating effective antibiotic policies and developing new
antimicrobial agents.
[Back to top] OXA-Type
b-Lactamases.
Thierry Naas and Patrice Nordmann.
The OXA-type (oxacillin-hydrolysing) enzymes are widespread and have
been mostly described in Enterobacteriaceae and in P. aeruginosa.
They usually confer resistance to amino- and ureidopenicillin and possess
high-level hydrolytic activity against cloxacillin, oxacillin, and methicillin.
Their activities are weakly inhibited by clavulanic acid but sodium chloride
(NaCl) possesses a strong inhibition activity. Oxacillin-hydrolysing b-Lactamases
belong to Ambler class D and thus possess an active serine site as classes
A and C b-Lactamases. Overall amino-acid identities
between class D and class A or class C b-Lactamases
is about 16%. Until now, 24 Ambler class D enzymes, named OXA-1 to OXA-22,
AmpS and LCR-1, have been characterised, either by sequence and/or by biochemical
analyses, but for none of them a three dimensional structure is yet available.
While some oxacillinases present a significant degree of amino-acid identity
(for example, OXA-1 and OXA-4; OXA-10 (PSE-2) derivatives; OXA-2 and OXA-3),
most of them are only weakly related (20% to 30% amino-acid identity).
Oxacillinases usually display a restricted-spectrum phenotype. However
extension of their spectrum towards oxyimino cephalosporins and/or imipenem
has recently been observed mostly as a consequence of point mutations in
OXA-2 or OXA-10 derivatives. Their frequent plasmid- and/or integron-location
provide them a mean for a wide diffusion.
[Back to top] Regulation
of Inducible AmpC Beta-Lactamase Expression Among Enterobacteriaceae. N.D.
Hanson and C.C. Sanders.
AmpC b-lactamases are active-site serine
enzymes that are primarily cephalosporinases. In many gram negative organisms,
including Enterobacter spp.,Citrobacter freundii, Serratia marcescens,
Morganella morganii and Pseudomonas aeruginosa, the expression
of chromosomal ampC genes is low but inducible in response to b-lactams
and other stimuli. The current working model for AmpC induction requires
exposure of bacterial cells to
b-lactam drugs
or other stimuli and is linked to the cell wall recycling pathway. Induction
of ampC appears to involve several gene products associated with
this pathway. These gene products include AmpR, AmpD, and AmpG. In addition,
anhydro forms of cell wall precursor muropeptides are believed to act as
cofactors for AmpC induction. These cofactors bind to the DNA binding protein,
AmpR, and define the role of AmpR as activator. Recent debate has ensued
in the literature as to the identification of the precursor muropeptide
involved in the activation process. Two candidate muropeptides include
1,6-anhydro-N-acetylmuramic acid L-Ala-D-Glu-meso-diaminopimelic acid (anhydro-MurNAc-tripeptide)
and anhydro-MurNAc-L-Ala-D-Glu-meso-diaminopimelic acid- D-Ala-D-Ala (pentapeptide).
The intent of this review is to address the general mechanism involved
in AmpC induction. In doing so, the genes and gene products required for
the process of AmpC induction are described. In addition, we review the
data addressing cell wall recycling as it relates to AmpC induction.
[Back to top] The Reactivity
of b-Lactams, the Mechanism of Catalysis and
the Inhibition of b-Lactamases. Michael I. Page.
Four membered b-Lactam rings do not show
unusual reactivity compared with their acyclic amide analogues and there
is no evidence of concerted mechanisms for nucleophilic substitution reactions
at the carbonyl centre. The identity of the general base/acid catalyst
in the serine b-Lactamases, which catalyse the
hydrolysis of b-Lactams, is unknown. There are
no ideal transition state analogue inhibitors for these enzymes which involve
several intermediates and transition states. The class C serine b-Lactamase
enhances the rate of phosphonylation of its active site serine residue
by a similar magnitude to the enzyme rate enhancement factor for the hydrolysis
of b-Lactams. Comparisons are made between the
stereochemical consequences of tetrahedral and trigonal bipyramidal intermediates
for hydrolysis and phosphonylation respectively. Class B zinc b-Lactamases
are inhibited by thiol dipeptides with a D configuration at the cysteine
centre analogous to the L configuration at C6 in penicillins. The mechanism
of hydrolysis catalysed by the metallo-b-Lactamases
probably involves a di-anionic tetrahedral intermediate stabilised by zinc(II).
[Back to top] Class B
b-Lactamases:
the Importance of Being Metallic. Julia A. Cricco and Alejandro J. Vila.
The structural and functional features of class B b-Lactamases,
which are metal-dependent, are reviewed in this article. Enzymes from different
bacterial strains exhibit a common fold and sequence similarity in their
active sites. However, the protein scaffold fine tunes the metal binding
affinity and substrate selectivity. In this way, some metallo-b-Lactamases
seem to be functional with only one Zn(II) equivalent per enzyme, whereas
others require a binuclear active site. The sequence similarity leads to
a subdivision of these enzymes into three subclasses. The substrate specificities
are rather broad, except for enzymes belonging to subclass B2. Some inhibitors
have been designed and tested, but none of them is able to exhibit a broad
spectrum against these enzymes.
[Back to top] Structural
and Mechanistic Aspects of Evolution of b-Lactamases
and Penicillin-Binding Proteins. Irina Massova and Shahriar Mobashery.
Penicillin-binding proteins (PBPs) and b-Lactamases
are related enzymes, the former are the targets for b-Lactam
antibiotics and the latter are resistance enzyme to these antibiotics.
The two families of enzymes share structural topologies and certain mechanistic
features. However, these classes of enzymes have diversified substantially
and have broadened the reaction repertoire for their catalytic properties.
This report addresses the issues of the evolution of function of these
proteins.
[Back to top] Recent Advances
in the Chemistry of b-Lactam Compounds as Selected
Active-site Serine b-Lactamase Inhibitors. Oreste
A. Mascaretti, Gerardo O. Danelon, Eduardo L. Setti, María Laborde
and Ernesto G. Mata.
The b-Lactamases catalyze the hydrolysis
of the b-Lactam bond of a variety of b-Lactam
antibiotics destroying their antibacterial activity. During the last decades,
there has been an inexorable spread of b-Lactamase
genes into species that previously were not known to possess them.
One approach to combat the action of the b-Lactamase is to inhibit the enzyme. However, inhibition of b-Lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use.
This review takes recent examples of synthetic b-Lactam compounds developed as active-site serine b-Lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-Lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.
[Back to top] Solid-phase
and Combinatorial Synthesis in b-Lactam Chemistry.
Ernesto G. Mata.
Combinatorial chemistry has became a core technology for the rapid
development of novel lead compounds in the pharmaceutical industry and
for the optimization of therapeutic efficacy. The effort to prepare libraries
of compounds by combinatorial chemistry has led to an unprecedented growth
in solid phase organic synthesis (SPOS), particularly for the preparation
of non-oligomeric small molecules. In this context, the clinically valuable
b-Lactam
compounds are very attractive targets for research using these new techniques.
In recent years, b-Lactam compounds have been
recognized not only as unique antibacterial agents but also as potent enzyme
inhibitors, drug delivery agents, and versatile synthetic intermediates.
This review gives a comprehensive up-date for the application of solid-phase
and combinatorial synthesis to b-Lactam compounds.