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1
Walter, Magnus Wilhelm. "Synthesis of metallo-#beta#-lactamase inhibitors." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360013.
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Pauff, James. "Fluorescence properties of metallo-beta-lactamase L1." Miami University Honors Theses / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1111003051.
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Bergstrom, Alexander R. "SPECTROSCOPIC AND MECHANISTIC STUDIES OF METALLO-BETA-LACTAMASE INHIBITORS AND THE STRUCTURE-FUNCTION RELATIONSHIP OF NEW DELHI METALLO-BETA-LACTAMASE VARIANTS." Miami University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami1524154064246174.
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Periyannan, Gopal Raj. "Characterization of the metallo-[beta]-lactamase L1 from Stenotrophomonas maltophilia." Oxford, Ohio : Miami University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1099689034.
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Higgins, Catherine. "Analysis of the tetrameric metallo-#beta#-lactamase, L1, from Stenotrophomonas maltophilia." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393011.
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Crawford, Patrick Anthony. "Characterization of ImiS, the metallo-[beta]-lactamase from Aeromonas veronii bv. sobria." Oxford, Ohio : Miami University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1069106986.
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Thesis (Ph. D.)--Miami University, Dept. of Chemistry and Biochemistry, 2003.<br>Title from first page of PDF document. Document formatted into pages; contains xi, 150 p. : ill. Includes bibliographical references.
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Hawk, Megan J. "Spectrocopic [sic] and mechanistic studies on metallo-[Beta]-lactamase Bla2 from Bacillus anthracis." Oxford, Ohio : Miami University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1229053358.
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Hu, Zhenxin. "Kinetic and spectroscopic studies of L1, the metallo-[beta]-lactamase from Stenotrophomonas maltophilia." Oxford, Ohio : Miami University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1218136291.
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Murphy, Deirdre M. "STUDIES OF THE METALLO BETA LACTAMASE CCrA FROM BACTERIODES FRAGILIS AND A DANSYLATED MONOCYCLIC BETA LACTAM (1-(5-DIMETHYLAMINO-1-NAPTHALENESULFONYL HYDRAZIDO)-3-ACETAMIDO-4-METHOXY-2-AZETIDINONE." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin990561318.
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Herron, Lissa. "Determining Which Tryptophan Residues Give Rise to Fluorescence Properties in the Metallo-Beta-Lactamase L1." Miami University Honors Theses / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1110916836.
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Chandrasekar, Sowmya. "Probing metal and substrate binding to metallo-[beta]-lactamase ImiS from Aeromonas sobria using site-directed mutagenesis." Oxford, Ohio : Miami University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1098134311.
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GONÇALVES, Diana Christina Pereira Santos. "Detecção de metalo beta lactamase em Pseudomonas aeruginosa isoladas de pacientes hospitalizados." Universidade Federal de Goiás, 2009. http://repositorio.bc.ufg.br/tede/handle/tde/1787.
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Previous issue date: 2009-02-18<br>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.<br>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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Gonçalves, Ana Lúcia Saraiva. "Avaliação da produção de β-lactamase em pseudomonas aeruginosa obtidas de dois Hospitais de Porto Alegre". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2005. http://hdl.handle.net/10183/24617.
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Objetivos: Avaliar o perfil de suscetibilidade, a prevalência da produção de AmpC, β-lactamase de espectro estendido (ESBL) e Metalo-β-lactamase (M-βla) em Pseudomonas aeruginosa obtidas de dois hospitais universitários distintos (ISCMPA e HCPA) em Porto Alegre. Em adição, tipagem molecular por PFGE foi realizada entre os isolados produtores de M-βla para avaliar a relação clonal. Métodos: Foi determinada a suscetibilidade de 238 isolados de P. aeruginosa para 8 agentes antimicrobianos, através do teste de disco-difusão, usando agar Müller-Hinton (MH) de acordo com “National Committee for Clinical Laboratory Standards” (NCCLS) . Todos isolados foram avaliados para produção de AmpC com o disco de imipenem (indutor) próximo ao disco de cefepima/ceftazdima (substrato). Um achatamento no halo de cefepime/ceftazidima pela indução da enzima pelo imipenem, indicava resultado positivo para AmpC. Todos isolados forma avaliados para a presença de ESBL através do teste de aproximação de disco com ceftazidima, cefepima, cefotaxima, ceftriaxona e ticarcilina-clavulanato como inibidor de β-lactamase. A produção de M-βla foi determinada através do teste de aproximação de discos de CAZ a discos impregnados com ácido2-mercatopropiônico (2-MPA). As taxas de resistência foram comparadas através do Teste Exato de Fisher. Valor de P<0,05 foi considerado estatisticamente significativo. Análise de macrorestrição com a enzima speI foi realizada em isolados produtores de M-βla. Resultados: As taxas de resistência para todos os agentes foram superiores entre os isolados obtidos na ISCMPA em relação aos do HCPA. A ceftazidima mostrou ser o antibiótico mais efetivo contra os isolados de ambos Hospitais (ISCMPA e HCPA) com taxa de resistência de 25,7% (ISCMPA) e 6,1% (HCPA). A expressão de AmpC foi observada em 190 isolados (83,7% HCPA e 77,1% ISCMPA). Não foi possível detectar a presença de ESBL entre todos as P. aeruginosa avaliadas em ambos hospitais. Foi observada a presença de M-βla em 28 isolados (20,0%) da ISCMPA. Mas não foi detectada M-βla em nenhuma P. aeruginosa do HCPA. A análise de macrorestrição mostrou que 14 de 16 P. aeruginosa Mβla positivas pertenciam a um clone (denominado clone A), e seus subclones. Apenas dois outros clones (B e C) foram identificados em um isolado cada.<br>Objectives: To evaluate susceptibility profile, the prevalence of extendedspectrum β-lactamases (ESBL) production, AmpC and Metallo-β-lactamases (M-βla) in Pseudomonas aeruginosa obtained from two distinct hospitals (ISCMPA and HCPA) in Porto Alegre, Brazil. In addiction, molecular typing by PFGE was perfomed among isolates producing M-βla in order to evaluate probably clonal relatedness. Methods: The susceptibility of 238 P. aeruginosa to 8 antimicrobial agents was determined by the disk diffusion method, using Müller-Hinton agar (MH) in accordance with “National Committee for Clinical Laboratory Standards” guidelines. All isolates were evaluated for AmpC production with the imipenem disk (strong inducer) near of the cefepime/ceftazidime disk (substrate). A blunting of the cefepime/ceftazidime zone by imipenem-induced enzyme, indicated positive result for AmpC. All isolates were evaluated for ESBL production by disk approximation test with ceftazdime, cefepime, cefotaxime, ceftriaxone plus ticarcillin-clavulanate as inhibitor. M-βla production was determined by disk approximation test with disks containing CAZ and 2-mercatopropionic acid (2-MPA). The results were compared by the Fisher’s Exact Test. Macrorestriction analysis by SpeI, followed by PFGE, was perfomed in isolates M-βla positive. The resistance rates were compared by The Fisher’s Exact Test. P values < 0.05 were considered to be statistically significant. Results: The resistance rates to all antimicrobial agents were higher among isolates obtained from ISCMPA than those obtained from HCPA. The ceftazidime was the more active antibiotic against the isolates in both hospitals with resistance rates of 25,7% (ISCMPA) and 6,1% (HCPA). The derepression of AmpC was observed in 190 isolates (83,7% HCPA and 77,1% ISCMPA). It was not possible to detect the presence of ESBL among all P. aeruginosa evaluated in both hospitals. Positive results for M-βla production were observed in 28 isolates (20,0%) from ISCMPA. But none M-βla production was identified in P. aeruginosa from HCPA. The macrorestriction analysis by PFGE, showed that 14 of 16 M-βla positive P. aeruginosa beloneed to one clone (named clone A) and its subclones.Only two others clones (B and C) were identified in one isolate each.
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yang, hao. "SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY." Miami University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=miami1437835452.
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Fleming, Maria Emília de Castro Kling. "Análise da resistência a antimicrobianos em microrganismos isolados de hemoculturas em hospitais de Niterói." Niterói, 2017. https://app.uff.br/riuff/handle/1/3356.
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Fleming, Maria Emília de Castro Kling [Dissertação, 2011].pdf: 3850457 bytes, checksum: 76e7a64373d2898f956190ecd2aa26c3 (MD5)<br>Introdução: As infecções de corrente sanguínea estão entre as mais graves
infecções, principalmente se causadas por microrganismos resistentes a
antimicrobianos. O objetivo deste estudo foi avaliar a prevalência e o perfil de
resistência de microrganismos isolados em hemoculturas em um hospital público e
outro privado localizados em Niterói, Rio de Janeiro, Brasil.
MÉTODOS: O estudo foi conduzido em um hospital geral de natureza pública com
227 leitos e um hospital geral, privado contendo 123 leitos, entre Agosto de 2009 a
Agosto de 2010. Todas as amostras provenientes de pacientes maiores de 18 anos
foram consecutivamente coletadas após identificação por métodos de rotina de cada
laboratório de microbiologia. As cepas de E. coli, K. pneumoniae, K. oxytoca e P.
mirabilis foram testadas quanto a produção de ESBL (Extended Spectrum Betalactamase)
de acordo com as recomendações do CLSI. As enterobactérias foram
testadas quanto a produção de carbapenemases pelo teste modificado de Hodge
(CLSI). As amostras de P. aeruginosa foram testadas para a produção de MBLs pelo
teste fenotípico de disco combinado. A reação em cadeia da polimerase (PCR) foi
utilizada para a detecção dos genes (blaIMP, blaVIM, blaSPM), relacionados com a
produção de metalo-beta-lactamases (MBLs). A similaridade genética entre as cepas
de P. aeruginosa foi avaliada pela técnica de eletroforese em gel de campo pulsado
(PFGE). RESULTADOS: Foram coletadas 195 amostras de microrganismos isolados
em hemoculturas no hospital público e 123 amostras no hospital privado. Os nãofermentadores
foram a maior causa de bacteremias na unidade de terapia intensiva
(UTI) da instituição pública. As enterobactérias foram os microrganismos mais
prevalentes nas enfermarias da unidade privada. No hospital público foram
detectadas amostras produtoras de ESBL, enquanto no hospital privado foram
identificadas cepas produtoras de carbapenemases. Dentre as cepas de P.
aeruginosa, 40 amostras foram testadas para a produção de MBLs. Treze cepas
(32,5%) foram positivas no teste fenotípico e no PCR, todas positivas para o gene
blaSPM-1, sendo que apenas uma foi proveniente da instituição pública e 12 do
hospital particular. Nenhuma amostra carreadora dos genes blaIMP-1 e blaVIM-2 foram
detectadas. Os resultados de PFGE mostraram que todas as cepas carreadoras do
gene blaSPM-1, isoladas no hospital privado, foram geneticamente relacionadas
(Pulsotipo A), o que pode indicar uma transmissão cruzada entre os pacientes e
profissionais de saúde. CONCLUSÕES: As características dos microrganismos
isolados em hemoculturas variou entre as unidades de internação e entre os
hospitais, demonstrando que os dados locais podem orientar a terapia
antimicrobiana e as medidas de controle e prevenção das infecções. Devido ao
impacto das infecções de corrente sanguínea e a presença de microrganismos
resistentes no ambiente hospitalar, estudos adicionais e medidas de vigilância são
necessárias<br>Introduction: Bloodstream infections are one of the most serious bacterial
infections, especially if caused by resistant microorganisms. The purpose of this
study was to assess the prevalence and resistance profile of pathogens isolated from
blood cultures in a public and a private hospital of Niterói, Rio de Janeiro, Brazil.
METHODS: A case-series of patients with blood stream infection was conducted at a
227-bed public general hospital and at a 123-bed private general hospital from
August 2009 to August 2010. All isolates were consecutively detected from patients
minimum age of 18 years and identified by the routine methodology used at each
laboratory. Every E. coli, K. pneumoniae, K. oxytoca and P. mirabilis isolates were
tested for ESBL (Extended Spectrum Beta-lactamase) production using the CLSI
guidelines. The Enterobacteriaceae was tested for carbapenemase production using
the Modified Hodge test (CLSI). Every P. aeruginosa were tested for metallo-betalactamases
(MBLs) producing by the phenotypic method of combined disk. The
polymerase chain reaction (PCR) was used to detect the MβLs genes (blaIMP,
blaVIM, blaSPM). The genetic similarity between the strains was evaluated in
samples which were positive for MBLs using the pulsed field gel electrophoresis
technique (PFGE).
RESULTS: Were collected 195 samples of microorganisms isolated in blood cultures
in the public hospital and 123 samples in the private hospital. The non-fermentatives
were the major cause of bacteremia in the ICU of public hospital. The
Enterobacteriaceae were the most prevalent in the the wards of private hospital. In
the public hospital, we found strains producing ESBL and in the private hospital,
strains producing carbapenemase. Forty samples of P. aeruginosa were tested for
MBL producing. Thirteen strains (32,5%) were positive in phenotypic test and in PCR,
every sample were positive for blaSPM-1, and only one was from the public
institution and 12 of the particular hospital. No blaIMP-1 and blaVIM gene were
detected. The PFGE analysis showed that all blaSPM-1 gene-carrying strains
isolated in private hospital were genetically related (Pulsetype A), suggesting a cross
transmission between patients and health professionals.
CONCLUSIONS: The characteristics of the microorganisms isolated from blood
culture varied from hospital to hospital and between inpatient units, showing that
local data can help with therapeutic choices and with the prevention and control of
infection. Due to the impact of bloodstream infections and the presence
of resistant microorganisms in the hospitals, additional studies and monitoring
measures are necessary
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VALLONE, ALESSANDRA. "INVESTIGATION OF NOVEL THERAPEUTIC TOOLS AGAINST INFECTIOUS DISEASES Part 1. Medicinal Chemistry Investigation of MMV019918 Derivatives as Dual Schizonticide And Gametocytocidal Agents Against Plasmodium falciparum Part 2. Investigation of 5-Aryl-Heterocycles As Potential Inhibitors of Metallo beta-Lactamase Enzymes." Doctoral thesis, Università di Siena, 2017. http://hdl.handle.net/11365/1004943.
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Among infectious diseases, two large groups have great clinical relevance: parasitic and bacterial
infections. Belonging to the first category is malaria, caused by the parasite Plasmodium
falciparum. Transmission of Plasmodium parasites between humans and Anopheles mosquitoes is
one of the most important contributors to the global impact of malaria and to the difficulties
encountered in eliminating this parasite1
. Gametocytogenesis, the process by which merozoites
switch from asexual replication to produce male and female gametocytes, represents a critical step
in malaria transmission and Plasmodium genetic diversity. Still too little is known about the
biochemical events that regulate gametocytogenesis and there are few existing drugs able of
inhibiting the gametocytes development and block malaria transmission2
. To encourage drug
discovery and research, the non-profit foundation Medicines for Malaria Venture (MMV) has
provided a library of 400 compounds that present antimalarial activity in the micromolar range, but
their molecular targets and mode of action are not necessarily known3
. Here we describe the
medchem investigation of one of the most promising hit compound included in this library,
MMV019918. MMV019918 has been highlighted in several in vitro studies for its promising antigametocyte
activity coupled to activity against schizonts. On the basis of its structure, the synthesis
of a new series of compounds with transmission-blocking activity has been designed. It has been
found very interesting the activity of one derivative NF2350 which resulted active also in the
standard membrane feeding assay (SMFA), to measure subsequent mosquito infection, and which
has an improved toxicological profile compared to MMV019918. A further investigation of NF2350
will allow us to optimize the transmission-blocking activity and to indentify its putative target.
Regarding bacterial infections, a critical issue to be addressed is bacterial resistance to antibiotics
and in particular to β-lactams. Metallo-β-lactamases (MBL) are a family of enzymes involved in the
widespread mechanisms of resistance to beta-lactam antibiotics, The diffusion of MBL-producing
isolates of Pseudomonas aeruginosa, a bacterial pathogen of primary relevance for both
nosocomial and chronic infections of the respiratory tracts in cystic fibrosis patients, is notably
increasing in some specific settings. No clinically useful MBLs inhibitors are currently available in
therapy3
Here we will present the design, synthesis, and biological investigation of a series of
functionalized 2-arylfuran compounds with sub-micromolar antiplasmodial activity, against both
asexual and sexual stages. Furthermore, appropriate decoration of this molecular scaffold allowed
to obtain activity against some isoforms of MBL (including IMP-1and NDM-1).
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Garrity, James D. "Characterization of L1, the metallo-B-lactamase from Stenotrophomonas maltophilia." Oxford, Ohio : Miami University, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1092150871.
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Galetti, Renata. "Estudo de Pseudomonas aeruginosa produtoras de metalo-beta-lactamase e de genes envolvidos na resistência aos carbapenêmicos." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-06102010-154221/.
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As metalo-beta-lactamases (MBL) são carbapenemases pertencentes à classe B de Ambler e ao grupo 3 de Bush-Jacoby, as duas classificações mais utilizadas atualmente. Essas enzimas conferem, às bactérias, resistência às cefalosporinas, penicilinas e carbapenêmicos, mas não conferem resistência ao monobactam aztreonam. Além disso, não são inibidas por inibidores de -lactamases comercialmente disponíveis, porém possuem sensibilidade ao ácido etileno diamino tetracético (EDTA) e ácido mercaptopropiônico (MPA). Atualmente são conhecidas nove subclasses de MBL: IMP,VIM, SPM, GIM, SIM, AIM, KHM, NDM e DIM. Essas MBL têm se tornado clinicamente importantes, principalmente, em Pseudomonas spp., Acinetobacter spp., e alguns gêneros da família Enterobacteriaceae. O principal objetivo desse trabalho foi a caracterização genética e epidemiológica de P. aeruginosa resistentes aos carbapêmicos, produtoras de MBL, isoladas no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto Universidade de São Paulo no período de abril a agosto de 2007. Das 54 P. aeruginosa estudadas, 24 foram positivas na triagem fenotípica para MBL e 5 apresentaram o gene blaSPM-1 detectado por PCR e confirmado pelo seqüenciamento. O inibidor mais eficiente na triagem fenotípica foi o EDTA. A baixa correlação entre o teste fenotípico e molecular pode ser explicada pela capacidade que o EDTA possui de aumentar a permeabilidade da membrana celular e assim tornar a bactéria sensível a baixas concentrações do antibiótico. Além disso, a diferença entre o número de isolados resistentes aos carbapenêmicos e/ou ceftazidima e os que apresentaram a MBL podem ser explicados pela associação de outros mecanismos de resistência, como hiperprodução de AmpC, redução da expressão de porinas e/ou aumento do efluxo de antibióticos. De acordo com o perfil de macrorrestrição obtido por eletroforese em campo pulsado as 5 linhagens produtoras de SPM-1 estão agrupadas em 3 perfis clonais distribuídos em diferentes clínicas no hospital não sendo identificado nenhum clone predominante. Finalizando, entre os isolados resistentes aos carbapenêmicos e/ou à ceftazidima a freqüência de P. aeruginosa produtoras de SPM-1 foi de 9,3%, indicando que as medidas aplicadas pela Comissão de Controle de Infecção Hospitalar (CCIH) desta instituição estão sendo eficientes, porém mesmo assim é necessário que a CCIH esteja sempre atenta a relatos de resistência aos carbapenêmicos pois, linhagens produtoras de MBL restringem muito as opções terapêuticas para infecções causas por elas.<br>Metallo-beta-lactamase (MBL) are carbapenemases which belong to the Bush-Jacoby-Medeiros group 3 and to the molecular class B, according Ambler. These two classifications are the most used nowadays. These enzymes confer microorganisms resistant to cephalosporins, penicillins and carbapenems, but not to aztreonam, a monobactam. Moreover, they are not inhibited by commercially available -lactamases inhibitors, but they are susceptible to EDTA and MPA. Currently this is known nine subclasses of MBL: IMP, VIM, SPM, GIM, SIM, AIM, KHM, NDM and DIM. These MBL became clinically important, especially in microorganisms such as Pseudomonas spp., Acinetobacter spp. and genera of the family Enterobacteriaceae. The main objective of this study was genetic and epidemiologic characterization of MBL-producing-P. aeruginosa, isolated in the Hospital of the Faculty of Medicine of Ribeirão Preto - University of São Paulo in the period from April to August 2007. Among the 54 P. aeruginosa studied, 24 were positive for phenotypic MBL screening and 5 presented blaSPM-1 gene, detected by PCR and confirmed by sequencing. The most efficient inhibitor in phenotypic screening was EDTA. The low correlation between phenotypic and molecular testing can be explained by the ability of EDTA to increase the permeability of cell membranes and rendering the bacteria as sensitive to low concentrations of antibiotic. Furthermore, the difference between number of isolates carbapenem resistant and / or ceftazidime resistant and the number of MBL-producing-P. aeruginosa can be explained by the association with other resistance mechanisms, such as AmpC overproduction, reduced expression of porins and / or increased antibiotics efflux. According to profile of macrorestriction after pulsed-field gel electrophoresis, five SPM-1-producing-P. aeruginosa are grouped in three different clonal profiles. These clonal strains were proceeded from different clinics at the hospital and no predominant clone was identified. Finally, among the carbapenems and/or ceftazidime resistant isolates the frequency of SPM-1-producing-P. aeruginosa was 9.3%, suggesting that the hospital care of infection control has being effective.
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Sharma, Narayan Prasad. "STRUCTURE/FUNCTION STUDIES ON METALLO-B- LACTAMASE ImiS FROM Aeromonas bv. sobria." Oxford, Ohio : Miami University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1181583976.
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VanPelt, Jamie L. "NMR Studies of Klebsiella Pneumoniae Carbapenemase-2 Inhibition and Structural Characterization of New Delhi Metallo-β-Lactamase Variants and Ligand Complexes". Miami University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami1542725553898546.
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Mire, Joseph Andrew. "Application of Structure Activity Relationships of the Mycobacterium Tuberculosis Beta-Lactamase (BlaC) and the New Delhi Metallo-Beta-Lactamase (NDM-1) to Combating Beta-Lactamase Mediated Drug Resistance." Thesis, 2013. http://hdl.handle.net/1969.1/151238.
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β-lactamase enzymes catalyze the irreversible hydrolysis of the four-membered cyclic amide ring characteristic of β-lactam antibiotics rendering them inactive and useless against pathogenic bacteria. Understanding structure activity relationships between β-lactam antibiotics and β-lactamases is important for designing novel β-lactams, β-lactamase inhibitors, and β-lactam-based fluorescent probes for rapid diagnosis of β-lactam antibiotic resistant infections.
The first half of this study focuses on the class A β-lactamase BlaC from Mycobacterium tuberculosis (Mtb) and addresses intermolecular interactions between BlaC and substrates, inhibitors, and biosensors that influence their kinetic parameters with BlaC and activities against Mtb. The substrate structure activity relationship explained the molecular basis for differential innate resistance of Mtb to faropenem, biapenem, and tebipenem by showing the interactions between BlaC and the lactams that govern differential acyl-intermediate stability and affinity. The inhibitor structure activity relationship revealed features of the BlaC active site that can be exploited to enhance binding and inhibition of BlaC by benzoxaboroles, and demonstrates their utility as potentiators of β-lactam antibiotic activity against Mtb. BlaC-specific β-lactam based fluorescent probes were designed and optimized for Mtb detection. Their utility was demonstrated by detecting down to 10 colony forming units of bacillus Mycobacterium bovis Calmette–Guérin (BCG) in human sputum.
The second half of this study focuses on the New Delhi Metallo-β-lactamase-1 (NDM-1), which is rapidly generating bacterial resistance to nearly all β-lactams. The NDM-1 gene encodes a class B1 metallo-β-lactamase enzyme. Purified recombinant NDM-1 was biochemically and biophysically characterized. The crystal structures of apo and monometalated NDM-1 provided structural insight into metal binding and the promiscuous enzymatic activity of NDM-1. Mechanistic details of the NMD-1 reaction were examined by comparing crystal structures of NDM-1 in complex with an unhydrolyzed β-lactam substrate and with hydrolyzed products. These structures were used for quantum mechanics / molecular mechanics simulations to estimate the free energy along the β-lactamase reaction coordinate. The results suggest that NDM-1 uses bulk water as the nucleophile that attacks the β-lactam ring, and a coordinated hydroxide ion or water molecule as the catalytic base depending on pH.
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Costa, Miguel Ângelo Canas Portela. "Computational studies for the discovery of novel inhibitors of metallo beta-lactamases as therapeutic targets for antibiotic resistance." Master's thesis, 2017. http://hdl.handle.net/10316/83757.
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Dissertação de Mestrado em Design e Desenvolvimento de Fármacos apresentada à Faculdade de Farmácia<br>O principal mecanismo de resistência a beta-lactâmicos é a hidrólise mediada por beta-lactamases (BL). Assim, a principal estratégia para ultrapassar a acção destas enzimas é a terapêutica combinada com moléculas inibidoras que, apesar de terem pouca ou nenhuma actividade antimicrobiana, têm uma elevada afinidade com as BL, restabelecendo a eficácia da terapêutica antibiótica.As metalo-BL (MBL) são uma classe estruturalmente distinta de BL, com um espectro hidrolítico que abrange a maioria dos antibióticos beta-lactâmicos, não sendo inibidas eficazmente por nenhum inibidor. As MBL são cada vez mais isoladas em estirpes bacterianas responsáveis por infecções em humanos e a sua prevalência continuará a aumentar já que começam a ser codificadas por elementos genéticos móveis. É, assim, evidente a urgência do desenvolvimento de soluções que permitam restabelecer a eficácia aos antibióticos beta-lactâmicos.Nas últimas décadas, o estudo de inibidores de MBLs permitiu identificar algumas famílias de compostos com potencial para desenvolvimento de inibidores. Ainda não houve, no entanto, avanços que permitam o seu desenvolvimento clínico.Neste estudo desenvolvemos um modelo farmacofórico para filtrar uma biblioteca de compostos construída a partir das bases de dados NCI, ZINC e DrugBank seleccionando moléculas candidatas a desenvolvimento como inibidores da MBL IMP-1. De seguida, realizámos simulações de docking dos compostos com melhores resultados no screening farmacofórico até obtermos um conjunto final com as moléculas com mais afinidade para o receptor (n=212) e um sub-grupo com os 49 melhores compostos com grupos tiol. Num futuro próximo, estas moléculas passarão por um processo de screening in-vitro que permita avaliar a actividade inibitória para a MBL IMP-1.<br>Hydrolysis by beta-lactamases (BL) is one of the major mechanisms that drive resistance to beta-lactam antibiotics. The major strategy to overcome their activity is the use of inhibitors that have little to none antibiotic activity, but bind with greater affinity to BLs, allowing an effective antibiotic therapy. The metallo-BL (MBL), are a structurally distinct BL class that hydrolyse almost all classes of beta-lactams and are not inhibited by any marketed inhibitor. They are increasingly produced by clinical bacteria and their prevalence will keep growing as some types of MBL are encoded in mobile genetic elements. It is thus, evident, the need for solutions that allow beta-lactam antibiotics to keep their effectiveness.The study of inhibitors for MBLs has highlighted some classes of compounds potentially useful for the design of a successful inhibitor in the future. However, none have yet entered further development stages.In this study, we have developed a structure-based pharmacophore model to screen large compound databases (NCI, ZINC and DrugBank) for candidate ligands to IMP-1 MBL, followed by molecular docking simulations of the compounds best fitting the pharmacophore, until a final collection of the 212 distinct molecules with the best docking fitness and the best 49 thiol compounds was reached. In the near future, these molecules will be screened in vitro for inhibitory activity against IMP-1 ..........................................................................
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Carruthers, Thomas James. "Paramagnetism & structural biology : biochemical & biophysical analysis of imp-1 metallo-beta-lactamase." Phd thesis, 2014. http://hdl.handle.net/1885/125027.
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Resistance to beta-lactam antibiotics by pathogenic bacteria is a global concern. Typically arising between 2 and 3 years after the introduction of the antibiotic into clinical use, it is usually due to beta-lactamase activity. The gene for IMP-1, a metallo-beta-lactamase with two catalytic metal ions, is located on an extremely mobile integron element, enabling the rapid horizontal transfer of beta-lactam resistance between bacterial species, including genera of pathogenically relevant bacteria. Along with the absence of any viable metallo-beta-lactamase inhibitors, this gene mobility makes IMP-1 particularly problematic in the clinical environment. Chapter two of this thesis reports nuclear magnetic resonance (NMR) analysis of IMP-1. 90% of the backbone amide resonances of IMP-1 were assigned using conventional 3D NMR experiments along with selective isotope labelling using cell-free methods. IMP-1 was found to have a high affinity for iron through the course of this study. The iron form was structurally and biochemically characterised using several techniques. A 1.8 Angstrom crystal structure of the iron variant was solved, showing a tertiary structure almost identical to the previously solved X-ray structures of the di-zinc form. NMR analysis suggested subtle differences in structure and/or mobility between the two species. Observed paramagnetic NMR effects induced by the iron centre included paramagnetic relaxation enhancement (PRE), which located the metal centre in the active site. Pseudocontact shifts (PCS) were also evident and a magnetic susceptibility anisotropy tensor was calculated. Paramagnetic NMR methods concurred with anomalous X-ray scattering experiments, locating the metal-binding site of the iron ion. A protocol for the use of paramagnetic effects from the iron centre in a high-throughput drug screening is proposed. A novel method of generating perdeuterated proteins using cell-free protein synthesis with isotope-labelled amino acids is described in chapter three. Performing the cell-free reaction in H2O-based buffers avoids the need for back-exchange of protons onto the backbone amides, which would be required following expressions in D2O. This is particularly useful for cases where protein refolding is impossible, such as the IMP-1 metallo-beta-lactamase. For proteins that can be expressed in good yields, the cost difference compared to conventional isotope-labelling methods is minimal. This chapter includes a reproduction of the application note produced for Cambridge Isotope Laboratories. The use of hyperpolarising agents such as para-hydrogen has recently engendered much interest in the NMR community. This methodology promises up to 350-fold signal-to-noise improvements over conventional experiments that start with a Boltzmann thermal population. Chapter four of this thesis briefly documents the establishment of an in-house built para-hydrogen producing rig in preparation for future studies into hyperpolarisation techniques. A standard operating procedure for obtaining optimal yields is also included. Structure determination of chemical products isolated from natural sources is an essential part of the natural drug discovery process. Chapter five briefly documents how NMR was used in this step for a natural product with pro-angiogenic biological properties extracted from soybean extracellular fluids that proved difficult to identify via other methods.
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Huang, Victor Wei-Shyue. "Isolation and characterization of reaction intermediates of the CerA metallo-beta-lactamase under cryokinetic conditions /." 2003. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3097116.
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Selvi, A. Tamil. "Metallo-β-Lactamase, Phosphotriesterase And Their Functional Mimics". Thesis, 2009. https://etd.iisc.ac.in/handle/2005/994.
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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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Selvi, A. Tamil. "Metallo-β-Lactamase, Phosphotriesterase And Their Functional Mimics". Thesis, 2009. http://hdl.handle.net/2005/994.
Full textAbstract:
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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Kuo, Tsui-Ming, and 郭萃敏. "Electrochemical Grafting of Aryl Diazonium Compounds for Analysis of the New Delhi Metallo-beta-lactamase (NDM)-coding Gene." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/85059988439698104761.
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碩士<br>東海大學<br>化學系<br>103<br>The abuse of antibiotics increase pathogens to produce resistance gene then the multidrug resistance gene (MDR gene) emerged with the situation become worse. To prevent the MDR gene spreading, it have to make the right decision for taking the antibiotics. For this reason, we take the superbug having New delhi metallo-beta-lactamase (NDM) be the sample to develop an electrobiosensor which modified by electrochemical grafting diazonium compounds. Construct a rapid-modifying and precise platform to detect the blaNDM.
The accurate analysis was supported by detect two encoding gene from binding site of NDM and one specific gene of blaNDM, when simultaneously sensing these three genetic sequences to generate output current. On the other side, we synthesize two aniline compounds, 3-((4-aminophenyl)dimethylammonio)propane-1-sulfonate (SC) and 4-amino-N-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzamido)ethyl)benzamide (MD), to use the MD coupling the thiol-modified nucleotide probe, and SC to resist non-specific binding. Diazotized MD and SC to product both aryl diazonium compounds then using electrochemical grafting method to deposition two molecules on the gold electrode. Before to construct the MD and SC modified platform, we use the commercial compounds, para-phenylenediamine (PPDA) coupling m-maleimidobenzoyl-N-hydoxysuccinimide ester (MBS), and preparing the anti-fouling modified by self-assembly monolayer (SAM) system, then to analyze the electrochemical character of ary diazonium-modified electrode and the effect of modified concentration and cycles with nucleotide sequences detection. After that, consider the conditions of modified PPDA to deposite the MD and SC platform, then study the ways of modified for two compounds (two step or co-deposition) and the ratio of concentration with two compounds to compare the sensing.
Finally, this platform modified by co-deposition MD and SC with the ratio for 1:1 in total concentration 0.1 mM, then obtain the sensing for S/N ratio with 19. This way is better than two step modified process with higher S/N ratio and reproducible. In our research, we succeed using electrochemical grafting method to functionalized surface by diazonium compounds. Comparing to the traditional method of functionalized surface, self-assembly monolayer , the platform have short-term for modified, simple modifying-steps and few chemical material of using, and offer a nice or better electrobiosensor for detecting the MDR gene.
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Aljassim, Nada I. "Exploration of Low-Cost, Natural Biocidal Strategies to Inactivate New Delhi Metallo-beta-lactamase (NDM)-Positive Escherichia coli PI-7, an Emerging Wastewater-Contaminant." Diss., 2018. http://hdl.handle.net/10754/628072.
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Conventional wastewater treatment plants are able to reduce contaminant loads within regulations but do not take into account emerging contaminants. Antibiotic resistance genes and antibiotic resistant bacteria have been shown to survive wastewater treatment and remain detectable in effluents. The safety of treated wastewaters is crucial, otherwise unregulated and unmitigated emerging contaminants pose risks to public health and impede wastewater reuse.
This dissertation aimed to further understanding of emerging microbial threats, and tested two natural and low-cost tools for their mitigation: sunlight, and bacteriophages. A wastewater bacterial isolate, named E. coli PI-7, which is highly antibiotic resistant, carries the novel antibiotic resistance gene New Delhi metallo-beta-lactamase NDM-1 gene, and displays pathogenic traits, was chosen to model responses to the treatments.
Results found that solar irradiation was able to achieve a 5-log reduction in E. coli PI-7 numbers within 12 hours of exposure. However, the results also emphasized the risks from emerging microbial contaminants since E. coli PI-7, when compared with a non-pathogenic strain E. coli DSM1103 that has less antibiotic resistance, showed longer survival under solar irradiation. In certain instances, E. coli PI-7 persisted for over 6 hours before starting to inactivate, exhibited complex stress resistance gene responses, and activated many of its concerning pathogenicity and antibiotic resistance traits.
However, upon solar irradiation, gene expression results obtained from both E. coli strains also showed increased susceptibility to bacteriophages. Hence, bacteriophages were coupled with solar irradiation as an additional mitigation strategy. Results using the coupled treatment found reduced cell-wall and extracellular matrix production in E. coli PI-7. DNA repair and other cellular defense functions like oxidative stress responses were also impeded, rendering E. coli PI-7 more susceptible to both stressors and successfully hastening the onset of its inactivation.
Overall, the dissertation is built upon the need to develop strategies to further mitigate risks associated with emerging microbial contaminants. Solar irradiation and bacteriophages demonstrate potential as natural and low-cost mitigation strategies. Sunlight was able to achieve significant log-reductions in tested E. coli numbers within a day’s exposure. Bacteriophages were able to overwhelm E. coli PI-7’s capacity to resist solar inactivation while not affecting the indigenous microbiota.