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Etude des propriétés de repliement et de fixation du zinc de la métallo-beta-lactamase BcII de Bacillus cereus 569/H/9Jacquin, Olivier 06 May 2011 (has links)
Metallo-beta-lactamases (MBLs) are members of the metallohydrolases family and constitute a very effective resistance mechanism employed by bacteria to escape the action of most beta-lactam antibiotics. Emergence of acquired MBLs among pathogenic species represents a major clinical threat, especially since no efficient inhibitors are available. On the basis of their primary structures, these enzymes have been subdivided in three subclasses (B1, B2 and B3).
The enzyme studied in this work, termed BcII, is produced by Bacillus cereus, strain 569/H/9, and is the most studied MBL so far (class B1 ; 227 a.a. ; M.W. 24960 Da). It displays a binuclear active site centre, which can bind various metal ions (e.g. Co2+ and Cd2+), although Zn2+ is the natural cofactor used for beta-lactams hydrolysis.
The first part of this work was dedicated to the characterization of the equilibrium folding properties of both the apo and holo forms of BcII. We used a variety of biophysical techniques, including absorbance, circular dichroism and intrinsic fluorescence spectroscopy, nuclear magnetic resonance (NMR), and mass spectrometry (MS). Interestingly, optical measurements revealed that although the apo and dizinc species exhibit undistinguishable tertiary structural organizations, the metal-depleted enzyme shows a significant decrease in its α-helical content, presumably associated with enhanced flexibility. The holoenzyme was found to be much more stable than the zinc-depleted form. Whereas the latter unfold according to a simple two-state mechanism, unfolding of the holoenzyme was found to be non-cooperative, with the population of intermediate species showing 3D structures very similar to the native species.
Besides folding studies, we investigated the process of metal binding to BcII. Zinc binding was monitored using complementary techniques, including circular dichroism in the far UV, enzymatic activity measurements, competition with a chromophoric chelator, MS and NMR. Most noticeably, MS and NMR experiments, together with catalytic activity measurements demonstrated that two zinc ions bind cooperatively to the enzyme active site (with K1/K2 ≥ 5, indicating positive cooperativity) and hence that catalysis is associated with the dizinc enzyme species only. Furthermore, competitive experiments with the chromophoric chelator Mag-Fura-2 indicated K2 < 80 nM.
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Spectrocopic [sic] and mechanistic studies on metallo-[Beta]-lactamase Bla2 from Bacillus anthracisHawk, Megan J. January 2008 (has links)
Thesis (M.S.)--Miami University, Dept. of Chemistry and Biochemistry, 2008. / Title from first page of PDF document. Non-Latin script record Includes bibliographical references.
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STUDIES OF THE METALLO BETA LACTAMASE CCrA FROM <i>BACTERIODES FRAGILIS</i> AND A DANSYLATED MONOCYCLIC BETA LACTAM (1-(5-DIMETHYLAMINO-1-NAPTHALENESULFONYL HYDRAZIDO)-3-ACETAMIDO-4-METHOXY-2-AZETIDINONEMurphy, Deirdre M. 11 October 2001 (has links)
No description available.
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Kinetic and spectroscopic studies of L1, the metallo-[beta]-lactamase from Stenotrophomonas maltophiliaHu, Zhenxin. January 2008 (has links)
Thesis (Ph. D.)--Miami University, Dept. of Chemistry and Biochemistry, 2008. / Title from second page of PDF document. Includes bibliographical references.
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SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERYyang, hao 27 July 2015 (has links)
No description available.
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SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTSBergstrom, Alexander R. 20 April 2018 (has links)
No description available.
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Metallo-β-Lactamase, Phosphotriesterase And Their Functional MimicsSelvi, A Tamil 07 1900 (has links)
Metallohydrolases with dinuclear-zinc active sites perform many important biological hydrolytic reactions on a variety of substrates. In this regard, metallo-β-lactamases (mβ1, class B) represent a unique subset of zine hydrolases that hydrolyze the β-lactam ring in several antibiotics. The antibiotic resistance that results from this hydrolysis is becoming an increased threat for the clinical community. These metalloenzymes can hydrolyze a wide range of β-lactam substrates, such as cephamycins and imipenem that are generally resistant t the serine-containing β-lactamases. Therefore, the clinical application of the entire range of antibiotics is severely compromised in bacteria that produce mβls. Due to the lack of information on the mechanism of mβls, to-date, no clinically known inhibitors is there for mβls. In this present study, we synthesized several mono and dizinc complexes as models for the mβls and investigated the differences in their hydrolytic properties. This study supports the assumption that the second zinc in the dinuclear enzymes does not directly involve in the catalysis, but may orient the substrates for hydrolysis and the basic amino acid residues such as Asp and His may activate the zinc-bound water molecules, fulfilling the role of the second zinc in the mononuclear enzymes.
The effect of various side chains on the hydrolysis of some commonly used cephalosporin antibiotics by mβl from B.cereus is described. It is shown that the cephalosporins having heterocyclic thiol side chains are more resistance to mβl-mediated hydrolysis than the antibiotics that do not have such side chains. This is partly due to the inhibition of enzyme activity by the thiol moieties eliminated during the hydrolysis. It is also observed that the heterocyclic side chains in pure form inhibit the lactamase activity of mβl as well as its synthetic mimics. The mode of binding of these heterocyclic side chains to the zinc has been analyzed from the crystal structure of the tetranuclear zinc complexes. The theoretical studies suggest that the eliminated heterocyclic thiols undergo a rapid tautomerism to produce the corresponding thiones. These thiones are found to irreversibly inhibit the LPO-catalyzed iodination reaction. The reaction of various thiones with I2 leads to the formation of thione-iodine complexes similar to that of the most commonly used antithyroid drug methimazole(MMI). These observations suggest that some of the latest generation of antibiotics may show negative effects on thyroid gland upon hydrolysis.
Synthetic organophosphorus compounds have been used extensively as pesticides and petroleum additives. These compounds are very toxic to mammals and their widespread use in agriculture leads to serious environmental problems. Therfore, degradation of organophosphorus trimesters and remediation of associated contaminated sites are of worldwide concern. In this regards, the bacterial phsophotriesterase (PTE) enzyme plays an important role in degrading a wide range of organophosphorus esters and the active side of PTE has been shown to be very similar to that of mβl. This identification prompted us to check the hydrolysis of phosphotriesters by the mβl and its mimics. It has been observed that the dinuclear zine(II) complexes that do not allow a strong binding of phosphodiestes would be a better PTE mimics.
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Detecção de metalo beta lactamase em Pseudomonas aeruginosa isoladas de pacientes hospitalizados / Detecção de metalo beta lactamase em Pseudomonas aeruginosa isoladas de pacientes hospitalizados / Detecção de metalo beta lactamase em Pseudomonas aeruginosa isoladas de pacientes hospitalizados / Detecção de metalo beta lactamase em Pseudomonas aeruginosa isoladas de pacientes hospitalizadosGONÇALVES, Diana Christina Pereira Santos 18 February 2009 (has links)
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Previous issue date: 2009-02-18 / P. aeruginosa is frequently isolated in hospitals and the clinical importance has been
increased due to gravity of infections. The metallo-beta-lactamase (MBL) production is an
emergent mechanism of resistance in P. aeruginosa. The study aimed to determine the
antimicrobial susceptibility profile of P. aeruginosa isolated of patients admitted in a hospital
in Goiânia, to verify the MBL production by diffusion test and detect MBL genes by PCR
technique. A total of 75 samples were evaluated, isolated of various clinical samples, in the
period of January/2005 to January/2007. The biochemical identification was performed by
automation technique system (API 20E ®) and antimicrobial susceptibility profile by Kirby-
Bauer method. The 75 P. aeruginosa presented multi-drug resistance and, the resistance
profile was: 90.7% to ceftazidime: 30.7% to aztreonam, 97.3% to ciprofloxacin; 48.0% of
resistance to piperacilin/tazobactam, 88.0% to cefepime; amicacin, gentamicin and
tobramicina whit resistance profile of 78.7%, 84.0% and 77.4%, respectively. The MBL
production by difusion disc method was 46.7% (35/75). The gene blaSPM-1 was detected in 39
(52.0%) and gene blaIMP-1 in three (4.0%) isolates. The high frequency of P. aeruginosa
resistant and MBL production alert to necessity of control the dissemination of bacteria
multi-drug resistant in hospital, as well as the adoption of preventive actions and explanation
of the health workers about rational use of antibiotics. / P. aeruginosa é frequentemente isolada em ambientes hospitalares e sua importância clínica
têm aumentado devido à gravidade das infecções. A produção de metalo-beta-lactamase
(MBL) é um mecanismo de resistência emergente entre P. aeruginosa. O estudo teve como
objetivo determinar o perfil de suscetibilidade antimicrobiana de P. aeruginosa isoladas de
pacientes internados em um hospital de Goiânia, realizar a triagem fenotípica para verificar a
produção de MBL e detectar genes que codificam MBL pela técnica de PCR. Foram
avaliadas 75 amostras, isoladas de diversos sítios, no período de janeiro de 2005 a janeiro de
2007. A identificação bioquímica foi realizada pelo sistema API 20E e o antibiograma pelo
método de Kirby-Bauer. Todos os 75 isolados de P. aeruginosa apresentaram
multirresistência, 82,7% foram resistentes ao imipenem; ceftazidima 90,7%; aztreonam
30,7%; ciprofloxacina 97,3%; 48,0% de resistência a piperacilina/tazobactam, 88,0% ao
cefepime; amicacina, gentamicina e tobramicina, com resistência de 78,7%, 84,0% e 77,4%,
respectivamente. A produção de MBL pelo método de disco aproximação foi detectada em
46,7% (35/75). O gene blaSPM-1 foi detectado em 39 (52,0%) e o blaIMP-1 em três (4,0%)
amostras através da técnica de PCR. A frequência elevada de P. aeruginosa multirresistentes
e produtoras de MBL alerta para necessidade de controle da disseminação de resistência no
ambiente hospitalar, bem como a adoção de medidas preventivas e esclarecimento das
equipes de saúde sobre uso racional dos antimicrobianos.
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