Beta-Lactam Ring

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J Heesemann - One of the best experts on this subject based on the ideXlab platform.

  • [Mechanisms of resistance to Beta-Lactam antibiotics].
    Infection, 1993
    Co-Authors: J Heesemann
    Abstract:

    Beta-Lactam antibiotics share the structural feature of a Beta-Lactam Ring. This feature is responsible for inhibition of bacterial cell wall synthesis. The target molecules are peptidoglycan cross-linking enzymes (e.g. transpeptidases and carboxypeptidases) which can bind Beta-Lactam antibiotics (penicillin binding proteins, PBP). Bacterial cell death is initiated by Beta-Lactam antibiotic-triggered release of autolytic enzymes. In contrast to gram-positive bacteria (absence of an outer membrane) the antibiotic has to penetrate through porins of the outer membrane of gram-negative bacteria before touching PBP's. Bacterial resistance to Beta-Lactam antibiotics includes modification of porins (permeability barrier) and of targets (low affinity of PBP's for the drug), production of inactivating enzymes (Beta-Lactamases) and inhibition of release of autolytic enzymes. Moreover, bacteria have developed sophisticated genetic mechanisms to adapt to treatments with novel Beta-Lactam antibiotics. To allow successful antibiotic treatment of bacterial infection in the future, knowledge about antibiotic resistance mechanisms is required.

M Menendez - One of the best experts on this subject based on the ideXlab platform.

  • Interaction of Beta-Lactamases I and II from Bacillus cereus with semisynthetic cephamycins. Kinetic studies.
    The Biochemical journal, 1991
    Co-Authors: J Martin Villacorta, P Arriaga, J Laynez, M Menendez
    Abstract:

    The influence of C-6 alpha- or C-7 alpha-methoxylation of the Beta-Lactam Ring in the catalytic action of class A and B Beta-Lactamases has been investigated. For this purpose the kinetic behaviour of Beta-Lactamases I (class A) and II (class B) from Bacillus cereus was analysed by using several cephamycins, moxalactam, temocillin and related antibiotics. These compounds behaved as poor substrates for Beta-Lactamase II, with high Km values and very low catalytic efficiencies. In the case of Beta-Lactamase I, the substitution of a methoxy group for a H atom at C-7 alpha or C-6 alpha decreased the affinity of the substrates for the enzyme. Furthermore, the acylation of cephamycins was completely blocked, whereas that of penicillins was slowed down by a factor of 10(4)-10(5), acylation being the rate-determining step of the process.

  • Interaction of β-lactamases I and II from Bacillus cereus with semisynthetic cephamycins. Kinetic studies
    Biochemical Journal, 1991
    Co-Authors: J Martin Villacorta, P Arriaga, J Laynez, M Menendez
    Abstract:

    The influence of C-6 alpha- or C-7 alpha-methoxylation of the Beta-Lactam Ring in the catalytic action of class A and B Beta-Lactamases has been investigated. For this purpose the kinetic behaviour of Beta-Lactamases I (class A) and II (class B) from Bacillus cereus was analysed by using several cephamycins, moxalactam, temocillin and related antibiotics. These compounds behaved as poor substrates for Beta-Lactamase II, with high Km values and very low catalytic efficiencies. In the case of Beta-Lactamase I, the substitution of a methoxy group for a H atom at C-7 alpha or C-6 alpha decreased the affinity of the substrates for the enzyme. Furthermore, the acylation of cephamycins was completely blocked, whereas that of penicillins was slowed down by a factor of 10(4)-10(5), acylation being the rate-determining step of the process.

Timothy G. Palzkill - One of the best experts on this subject based on the ideXlab platform.

  • Molecular analysis of Beta-Lactamase structure and function
    International Journal of Medical Microbiology, 2002
    Co-Authors: Fahd K. Majiduddin, Isabel C. Materon, Timothy G. Palzkill
    Abstract:

    The extensive and sometimes irresponsible use of Beta-Lactam antibiotics in clinical and agricultural settings has contributed to the emergence and widespread dissemination of antibiotic-resistant bacteria. Bacteria have evolved three strategies to escape the activity of Beta-Lactam antibiotics: 1) alteration of the target site (e.g. penicillin-binding protein (PBPs), 2) reduction of drug permeation across the bacterial membrane (e.g. efflux pumps) and 3) production of Beta-Lactamase enzymes. The Beta-Lactamase enzymes inactivate Beta-Lactam antibiotics by hydrolyzing the peptide bond of the characteristic four-membered Beta-Lactam Ring rendeRing the antibiotic ineffective. The inactivation of the antibiotic provides resistance to the bacterium. Currently, there are over 300 Beta-Lactamase enzymes described for which numerous kinetic, structural, computational and mutagenesis studies have been performed. In this review, we discuss the recent work performed on the four different classes (A, B, C, and D) of Beta-Lactamases. These investigative advances further expand our knowledge about these complex enzymes, and hopefully, will provide us with additional tools to develop new inhibitors and antibiotics based on structural and rational designs.

Jean-marie Frère - One of the best experts on this subject based on the ideXlab platform.

  • Mutational analysis of the two zinc-binding sites of the Bacillus cereus 569/H/9 metallo-Beta-Lactamase.
    The Biochemical journal, 2002
    Co-Authors: Dominique De Seny, Jean-marie Frère, Michael I. Page, Christelle Prosperi-meys, Carine Bebrone, Gian Maria Rossolini, Philippe Noel, Moreno Galleni
    Abstract:

    The metallo-Beta-Lactamase BcII from Bacillus cereus 569/H/9 possesses a binuclear zinc centre. The mono-zinc form of the enzyme displays an appreciably high activity, although full efficiency is observed for the di-zinc enzyme. In an attempt to assign the involvement of the different zinc ligands in the catalytic properties of BcII, individual substitutions of selected amino acids were generated. With the exception of His(116)-->Ser (H116S), C221A and C221S, the mono- and di-zinc forms of all the other mutants were poorly active. The activity of H116S decreases by a factor of 10 when compared with the wild type. The catalytic efficiency of C221A and C221S was zinc-dependent. The mono-zinc forms of these mutants exhibited a low activity, whereas the catalytic efficiency of their respective di-zinc forms was comparable with that of the wild type. Surprisingly, the zinc contents of the mutants and the wild-type BcII were similar. These data suggest that the affinity of the Beta-Lactamase for the metal was not affected by the substitution of the ligand. The pH-dependence of the H196S catalytic efficiency indicates that the zinc ions participate in the hydrolysis of the Beta-Lactam Ring by acting as a Lewis acid. The zinc ions activate the catalytic water molecule, but also polarize the carbonyl bond of the Beta-Lactam Ring and stabilize the development of a negative charge on the carbonyl oxygen of the tetrahedral reaction intermediate. Our studies also demonstrate that Asn(233) is not directly involved in the interaction with the substrates.

  • Peptidase activity of Beta-Lactamases.
    Biochemical Journal, 1999
    Co-Authors: Noureddine Rhazi, Moreno Galleni, Michael I. Page, Jean-marie Frère
    Abstract:

    Although Beta-Lactamases have generally been considered as being devoid of peptidase activity, a low but significant hydrolysis of various N-acylated dipeptides was observed with representatives of each class of Beta-Lactamases. The kcat/Km values were below 0.1 M(-1). s(-1), but the enzyme rate enhancement factors were in the range 5000-20000 for the best substrates. Not unexpectedly, the best 'peptidase' was the class C Beta-Lactamase of Enterobacter cloacae P99, but, more surprisingly, the activity was always higher with the phenylacetyl- and benzoyl-d-Ala-d-Ala dipeptides than with the diacetyl- and alpha-acetyl-l-Lys-d-Ala-d-Ala tripeptides, which are the preferred substrates of the low-molecular-mass, soluble dd-peptidases. A comparison between the Beta-Lactamases and dd-peptidases showed that it might be as difficult for a dd-peptidase to open the Beta-Lactam Ring as it is for the Beta-Lactamases to hydrolyse the peptides, an observation which can be explained by geometric and stereoelectronic considerations.

  • Interactions between Active-Site-Serine Beta-Lactamases and Compounds BeaRing a Methoxy Side Chain on the Alpha-Face of the Beta-Lactam Ring: Kinetic and Molecular Modelling Studies
    Biochemical Journal, 1993
    Co-Authors: André Matagne, Josette Lamotte-brasseur, Georges Dive, James R. Knox, Jean-marie Frère
    Abstract:

    The interactions between three class A Beta-Lactamases and compounds beaRing a methoxy side chain on the alpha-face of the Beta-Lactam Ring (cefoxitin, moxalactam and temocillin) have been studied. When compared with the situation prevailing with good substrates, both acylation and deacylation steps appeared to be severely impaired. Molecular modelling studies of the structures of the Henri-Michaelis complexes and of the acyl-enzymes indicate a major displacement of the crystallographically observed water molecule which connects the glutamate-166 and serine-70 side chains and underline the role of this water molecule in both reaction steps.

Jacqueline Marchand-brynaert - One of the best experts on this subject based on the ideXlab platform.

  • Adsorption properties of the penicillin derivative DTPA on gold substrates
    ChemPhysChem, 2007
    Co-Authors: Laurent Dreesen, Christophe Silien, Cédric Volcke, Yannick Sartenaer, Paul Thiry, André Peremans, Jérôme Grugier, Jacqueline Marchand-brynaert, Alain Brans, Stana Grubisic
    Abstract:

    Despite the large number of articles and patents dealing with penicillin and other Beta-Lactam antibiotics, there have been no reports about the self-assembly of such substances as monolayers on gold surfaces. The main reason stems from the high reactivity of the Beta-Lactam Ring, which hinders the development of molecules possessing this entity together with a metal-anchoRing function. Herein, we present the synthesis of a novel molecule, 6-[(R,S)-5-(1,2-dithiolan-3-yl)pentanoyl-amino]-penicillanic acid, which combines the Beta-Lactam Ring and a metal-anchoRing group. Using spectroscopic tools, we demonstrate the chemisorption of this compound on gold as self-assembled monolayers without any alteration of the penicillin pharmacophore and document its reactivity towards a penicillin-binding protein, BlaR-CTD. Our work is a preliminary step towards the development of new biosensors and well-ordered protein arrays, both based on the high affinity of penicillin for penicillin-binding proteins.

  • 1β-Methylcarbapenem intermediates via the thiolysis of a Meldrum's precursor
    Tetrahedron, 2001
    Co-Authors: Christophe Jacopin, Mathieu Laurent, Marc Belmans, Luc Kemps, Marcel Cérésiat, Jacqueline Marchand-brynaert
    Abstract:

    5-{3-[1-(tert-Butyidimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}-2,2,5-trimethyl-[1,3]dioxane-4,6-dione (3) has been submitted to nucleophilic attack with various nucleophiles. Meldrum's moiety transesterification, C4-substitution, beta -lactam Ring opening and Meldrum's moiety decarboxylation were observed. Reaction of 3 with ethanethiol and dimethylaminopyridine in ethanol quantitatively furnished ethyl 2-{3-[1-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-azetidin-2-yl}-thiopropionate as the 1:1 mixture of beta (7a) and alpha (8a) diastereoisomers. (C) 2001 Elsevier Science Ltd. All rights reserved.

  • Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors
    Tetrahedron, 1999
    Co-Authors: Cécile Beauve, Michèle Bouchet, Roland Touillaux, Jacques Fastrez, Jacqueline Marchand-brynaert
    Abstract:

    A series of monocyclic azetidinones were prepared, beaRing, at position C-3, an acetylamino or a bromo substituent, at position N-1, a carboxymethyl group protected as p-nitrobenzyl ester (PNB) and alpha-functionalized with a potential leaving group (LG). These structures were designed as potential suicide-inhibitors of enzymes containing a serine nucleophile in their active site. The Beta-Lactam Ring of these molecules was found to be stable in phosphate buffer (pH 7.5), but the PNB ester was rapidly cleaved. This constitutes a practical method of in situ deprotection. Depending on the nature of the LG group on the carboxymethyl chain, substitution of this group (LG = F) or decarboxylation (LG = SO2Ph) was observed under hydrolytic conditions. The 1,3-disubstituted azetidinones were inactive against Beta-Lactamases of classes A, B, C, and D. Three compounds behaved as weak reversible inhibitors of porcine pancreatic elastase (PPE). (C) 1999 Elsevier Science Ltd. All rights reserved.