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[PMID]:28287720
[Au] Autor:Tan L; Tao Y; Wang T; Zou F; Zhang S; Kou Q; Niu A; Chen Q; Chu W; Chen X; Wang H; Yang Y
[Ad] Endereço:State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
[Ti] Título:Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections.
[So] Source:J Med Chem;60(7):2669-2684, 2017 Apr 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.
[Mh] Termos MeSH primário: Antibacterianos/química
Antibacterianos/farmacologia
Farmacorresistência Bacteriana Múltipla
Bactérias Gram-Negativas/efeitos dos fármacos
Infecções por Bactérias Gram-Negativas/tratamento farmacológico
Monobactamas/química
Monobactamas/farmacologia
Tiazóis/química
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antibacterianos/sangue
Antibacterianos/uso terapêutico
Descoberta de Drogas
Escherichia coli/efeitos dos fármacos
Infecções por Escherichia coli/tratamento farmacológico
Seres Humanos
Infecções por Klebsiella/tratamento farmacológico
Klebsiella pneumoniae/efeitos dos fármacos
Masculino
Camundongos
Testes de Sensibilidade Microbiana
Monobactamas/sangue
Monobactamas/uso terapêutico
Piridonas/sangue
Piridonas/química
Piridonas/farmacologia
Piridonas/uso terapêutico
Ratos Sprague-Dawley
Relação Estrutura-Atividade
Tiazóis/sangue
Tiazóis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (BAL 30072); 0 (Monobactams); 0 (Pyridones); 0 (Thiazoles)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170314
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01261


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[PMID]:28137795
[Au] Autor:Moynié L; Luscher A; Rolo D; Pletzer D; Tortajada A; Weingart H; Braun Y; Page MG; Naismith JH; Köhler T
[Ad] Endereço:Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
[Ti] Título:Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii.
[So] Source:Antimicrob Agents Chemother;61(4), 2017 Apr.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against and Here, we investigated the mechanism of action of these molecules in We identified two novel TonB-dependent receptors, termed -PiuA and -PirA, that are required for the antimicrobial activity of both agents. Deletion of either or in resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from and their orthologues from were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of , forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens.
[Mh] Termos MeSH primário: Acinetobacter baumannii/efeitos dos fármacos
Acinetobacter baumannii/metabolismo
Antibacterianos/farmacologia
Pseudomonas aeruginosa/efeitos dos fármacos
Pseudomonas aeruginosa/metabolismo
[Mh] Termos MeSH secundário: Acinetobacter baumannii/genética
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Testes de Sensibilidade Microbiana
Monobactamas/farmacologia
Mutação/genética
Pseudomonas aeruginosa/genética
Tiazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (BAL 30072); 0 (Bacterial Proteins); 0 (Monobactams); 0 (Thiazoles)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE


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[PMID]:28107651
[Au] Autor:Braga D; Lackner G
[Ad] Endereço:Junior Research Group Synthetic Microbiology, Friedrich Schiller University at the Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Beutenbergstr.11a, 07745 Jena, Germany.
[Ti] Título:One Ring to Fight Them All: The Sulfazecin Story.
[So] Source:Cell Chem Biol;24(1):1-2, 2017 Jan 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this issue of Cell Chemical Biology, Li et al. (2017) report on the biosynthesis of the monobactam sulfazecin by Pseudomonas acidophila and hypothesize a novel mechanism of ß-lactam ring formation. As monobactam antibiotics are unaffected by some emerging resistance mechanisms (particularly metallo-ß-lactamases), this discovery opens prospects to engineer ß-lactam antibiotics against multi-drug resistant pathogens.
[Mh] Termos MeSH primário: Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Monobactamas/farmacologia
Pseudomonas/metabolismo
[Mh] Termos MeSH secundário: Estrutura Molecular
Monobactamas/biossíntese
Monobactamas/química
beta-Lactamas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Monobactams); 0 (beta-Lactams); X83NW9A0Y8 (sulfazecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE


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[PMID]:28017601
[Au] Autor:Li R; Oliver RA; Townsend CA
[Ad] Endereço:Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
[Ti] Título:Identification and Characterization of the Sulfazecin Monobactam Biosynthetic Gene Cluster.
[So] Source:Cell Chem Biol;24(1):24-34, 2017 Jan 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The monobactams, exemplified by the natural product sulfazecin, are the only class of ß-lactam antibiotics not inactivated by metallo-ß-lactamases, which confer bacteria with extended-spectrum ß-lactam resistance. We screened a transposon mutagenesis library from Pseudomonas acidophila ATCC 31363 and isolated a sulfazecin-deficient mutant that revealed a gene cluster encoding two non-ribosomal peptide synthetases (NRPSs), a methyltransferase, a sulfotransferase, and a dioxygenase. Three modules and an aberrant C-terminal thioesterase (TE) domain are distributed across the two NRPSs. Biochemical examination of the adenylation (A) domains provided evidence that L-2,3-diaminopropionate, not L-serine as previously thought, is the direct source of the ß-lactam ring of sulfazecin. ATP/PPi exchange assay also revealed an unusual substrate selectivity shift of one A domain when expressed with or without the immediately upstream condensation domain. Gene inactivation analysis defined a cluster of 13 open reading frames sufficient for sulfazecin production, precursor synthesis, self-resistance, and regulation. The identification of a key intermediate supported a proposed NRPS-mediated mechanism of sulfazecin biosynthesis and ß-lactam ring formation distinct from the nocardicins, another NRPS-derived subclass of monocyclic ß-lactam. These findings will serve as the basis for further biosynthetic research and potential engineering of these important antibiotics.
[Mh] Termos MeSH primário: Monobactamas/biossíntese
Família Multigênica/genética
Pseudomonas/metabolismo
[Mh] Termos MeSH secundário: Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos
Conformação Molecular
Monobactamas/química
Monobactamas/farmacologia
Peptídeo Sintases/genética
Peptídeo Sintases/metabolismo
Pseudomonas/genética
beta-Lactamas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Monobactams); 0 (beta-Lactams); EC 6.3.2.- (Peptide Synthases); X83NW9A0Y8 (sulfazecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161227
[St] Status:MEDLINE


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[PMID]:27795378
[Au] Autor:Vandavasi VG; Langan PS; Weiss KL; Parks JM; Cooper JB; Ginell SL; Coates L
[Ad] Endereço:Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
[Ti] Título:Active-Site Protonation States in an Acyl-Enzyme Intermediate of a Class A ß-Lactamase with a Monobactam Substrate.
[So] Source:Antimicrob Agents Chemother;61(1), 2017 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The monobactam antibiotic aztreonam is used to treat cystic fibrosis patients with chronic pulmonary infections colonized by Pseudomonas aeruginosa strains expressing CTX-M extended-spectrum ß-lactamases. The protonation states of active-site residues that are responsible for hydrolysis have been determined previously for the apo form of a CTX-M ß-lactamase but not for a monobactam acyl-enzyme intermediate. Here we used neutron and high-resolution X-ray crystallography to probe the mechanism by which CTX-M extended-spectrum ß-lactamases hydrolyze monobactam antibiotics. In these first reported structures of a class A ß-lactamase in an acyl-enzyme complex with aztreonam, we directly observed most of the hydrogen atoms (as deuterium) within the active site. Although Lys 234 is fully protonated in the acyl intermediate, we found that Lys 73 is neutral. These findings are consistent with Lys 73 being able to serve as a general base during the acylation part of the catalytic mechanism, as previously proposed.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Aztreonam/farmacologia
Monobactamas/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/química
Aztreonam/química
Domínio Catalítico
Cristalografia por Raios X
Testes de Sensibilidade Microbiana
Monobactamas/química
Pseudomonas aeruginosa/efeitos dos fármacos
Pseudomonas aeruginosa/enzimologia
beta-Lactamases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Monobactams); EC 3.5.2.6 (beta-Lactamases); G2B4VE5GH8 (Aztreonam)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161101
[St] Status:MEDLINE


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[PMID]:27736752
[Au] Autor:Cabot G; López-Causapé C; Ocampo-Sosa AA; Sommer LM; Domínguez MÁ; Zamorano L; Juan C; Tubau F; Rodríguez C; Moyà B; Peña C; Martínez-Martínez L; Plesiat P; Oliver A
[Ad] Endereço:Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
[Ti] Título:Deciphering the Resistome of the Widespread Pseudomonas aeruginosa Sequence Type 175 International High-Risk Clone through Whole-Genome Sequencing.
[So] Source:Antimicrob Agents Chemother;60(12):7415-7423, 2016 Dec.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Whole-genome sequencing (WGS) was used for the characterization of the frequently extensively drug resistant (XDR) Pseudomonas aeruginosa sequence type 175 (ST175) high-risk clone. A total of 18 ST175 isolates recovered from 8 different Spanish hospitals were analyzed; 4 isolates from 4 different French hospitals were included for comparison. The typical resistance profile of ST175 included penicillins, cephalosporins, monobactams, carbapenems, aminoglycosides, and fluoroquinolones. In the phylogenetic analysis, the four French isolates clustered together with two isolates from one of the Spanish regions. Sequence variation was analyzed for 146 chromosomal genes related to antimicrobial resistance, and horizontally acquired genes were explored using online databases. The resistome of ST175 was determined mainly by mutational events; resistance traits common to all or nearly all of the strains included specific ampR mutations leading to ampC overexpression, specific mutations in oprD conferring carbapenem resistance, or a mexZ mutation leading to MexXY overexpression. All isolates additionally harbored an aadB gene conferring gentamicin and tobramycin resistance. Several other resistance traits were specific to certain geographic areas, such as a streptomycin resistance gene, aadA13, detected in all four isolates from France and in the two isolates from the Cantabria region and a glpT mutation conferring fosfomycin resistance, detected in all but these six isolates. Finally, several unique resistance mutations were detected in single isolates; particularly interesting were those in genes encoding penicillin-binding proteins (PBP1A, PBP3, and PBP4). Thus, these results provide information valuable for understanding the genetic basis of resistance and the dynamics of the dissemination and evolution of high-risk clones.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Farmacorresistência Bacteriana Múltipla/genética
Genoma Bacteriano
Mutação
Filogenia
Pseudomonas aeruginosa/genética
[Mh] Termos MeSH secundário: Aminoglicosídeos/farmacologia
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Carbapenêmicos/farmacologia
Cefalosporinas/farmacologia
Células Clonais
Fluoroquinolonas/farmacologia
França/epidemiologia
Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Hospitais
Seres Humanos
Testes de Sensibilidade Microbiana
Monobactamas/farmacologia
Penicilinas/farmacologia
Porinas/genética
Porinas/metabolismo
Infecções por Pseudomonas/tratamento farmacológico
Infecções por Pseudomonas/epidemiologia
Infecções por Pseudomonas/microbiologia
Pseudomonas aeruginosa/classificação
Pseudomonas aeruginosa/efeitos dos fármacos
Pseudomonas aeruginosa/isolamento & purificação
Espanha/epidemiologia
beta-Lactamases/genética
beta-Lactamases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminoglycosides); 0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Carbapenems); 0 (Cephalosporins); 0 (Fluoroquinolones); 0 (MexXY protein, Pseudomonas aeruginosa); 0 (MexZ protein, Pseudomonas aeruginosa); 0 (Monobactams); 0 (Penicillins); 0 (Porins); 125267-46-1 (AmpR protein, Bacteria); 148412-32-2 (OprD protein, Pseudomonas aeruginosa); EC 3.5.2.6 (AmpC beta-lactamases); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161014
[St] Status:MEDLINE


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[PMID]:26976871
[Au] Autor:Straubinger M; Blenk H; Naber KG; Wagenlehner FM
[Ad] Endereço:Prokaryon Institute, Nuremberg, Germany.
[Ti] Título:Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam, against Uropathogens after Intravenous Administration in Healthy Subjects.
[So] Source:Antimicrob Agents Chemother;60(6):3309-15, 2016 Jun.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This annex study to a phase 1 study aimed to correlate urinary concentrations and bactericidal titers (UBTs) of BAL30072, a novel siderophore monosulfactam, in healthy subjects in order to evaluate which dosage of BAL30072 should be investigated in a clinical study on complicated urinary tract infection (UTI). Three cohorts of a total of 19 healthy male subjects were included in the add-on study and received the following BAL30072 dosages. The 1st cohort received 1 g once a day (q.d.) intravenously (i.v.) (1 h) on day 1 and 1 g thrice daily (t.i.d.) on day 2, the 2nd cohort received 2 g q.d. i.v. (1 h) on day 1 and 2 g t.i.d. on day 2, and the 3rd cohort received 1 g q.d. i.v. (4-h infusion) on day 8. Urine was collected up to 24 h after drug administration. UBTs were determined for seven Escherichia coli isolates (three wild type [WT], CTX-M-15, TEM-3, TEM-5, NDM-1), two Klebsiella pneumoniae isolates (WT, KPC), one Proteus mirabilis isolate (WT), and two Pseudomonas aeruginosa isolates (WT, VIM-1 plus AmpC). Urine drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median urinary excretions of BAL30072 ranged between 38% and 46% (3 cohorts). The median UBTs after i.v. administration of 1 or 2 g q.d. and after 1 or 2 g t.i.d. showed positive UBTs for 24 h after the lowest dosage (1 g q.d.) for 5 of 7 of the Enterobacteriaceae strains and after the higher dosage of 2 g administered i.v. t.i.d. for all strains tested. After i.v. infusion of 1 g over 4 h, positive UBTs were demonstrated for three E. coli strains for up to 12 h, for the K. pneumoniae (KPC) strain for up to 8 h, and for the P. aeruginosa (VIM-1 plus AmpC) strain for up to only 4 h. The minimal bactericidal concentrations (MBCs) of the E. coli (NDM-1) strain and the K. pneumoniae (WT) strain correlated well between broth and urine but did not correlate well for the two P. aeruginosa strains. BAL30072 exhibits positive UBTs for 24 h even after a dosage of 1 g administered i.v. q.d. for 5 of 7 Enterobacteriaceae strains and after 2 g administered i.v. t.i.d. for all strains except one P. aeruginosa strain (50% of the time). In general, the UBTs correlated well with the MICs of the Enterobacteriaceae but were lower for P. aeruginosa The clinical efficacy with a dosage regimen of BAL30072 of 2 g administered i.v. t.i.d. should be evaluated in the treatment of complicated UTI.
[Mh] Termos MeSH primário: Antibacterianos/uso terapêutico
Antibacterianos/urina
Monobactamas/uso terapêutico
Monobactamas/urina
Tiazóis/uso terapêutico
Tiazóis/urina
Infecções Urinárias/tratamento farmacológico
Infecções Urinárias/urina
[Mh] Termos MeSH secundário: Administração Intravenosa
Adulto
Antibacterianos/administração & dosagem
Cromatografia Líquida
Enterobacteriaceae/efeitos dos fármacos
Enterobacteriaceae/patogenicidade
Escherichia coli/efeitos dos fármacos
Escherichia coli/patogenicidade
Voluntários Saudáveis
Seres Humanos
Klebsiella pneumoniae/efeitos dos fármacos
Klebsiella pneumoniae/patogenicidade
Masculino
Testes de Sensibilidade Microbiana
Meia-Idade
Monobactamas/administração & dosagem
Proteus mirabilis/efeitos dos fármacos
Proteus mirabilis/patogenicidade
Espectrometria de Massas em Tandem
Tiazóis/administração & dosagem
Infecções Urinárias/microbiologia
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (BAL 30072); 0 (Monobactams); 0 (Thiazoles)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160316
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.02425-15


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[PMID]:26827160
[Au] Autor:Fu HG; Hu XX; Li CR; Li YH; Wang YX; Jiang JD; Bi CW; Tang S; You XF; Song DQ
[Ad] Endereço:Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
[Ti] Título:Design, synthesis and biological evaluation of monobactams as antibacterial agents against gram-negative bacteria.
[So] Source:Eur J Med Chem;110:151-63, 2016 Mar 03.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 µg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 µg/mL to 8 µg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.
[Mh] Termos MeSH primário: Antibacterianos/química
Antibacterianos/farmacologia
Bactérias Gram-Negativas/efeitos dos fármacos
Infecções por Bactérias Gram-Negativas/tratamento farmacológico
Monobactamas/química
Monobactamas/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Aztreonam/análogos & derivados
Aztreonam/síntese química
Aztreonam/farmacologia
Desenho de Drogas
Escherichia coli/efeitos dos fármacos
Seres Humanos
Klebsiella pneumoniae/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Modelos Moleculares
Monobactamas/síntese química
Relação Estrutura-Atividade
Tiazóis/síntese química
Tiazóis/química
Tiazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (BAL 30072); 0 (Monobactams); 0 (Thiazoles); G2B4VE5GH8 (Aztreonam)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160201
[St] Status:MEDLINE


  9 / 301 MEDLINE  
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[PMID]:26729500
[Au] Autor:Fernea A; Galleni M; Frère JM
[Ad] Endereço:Centre for Protein Engineering, Université de Liège, Liège, Belgium.
[Ti] Título:Kinetics of the Interaction between BAL29880 and LK157 and the Class C ß-Lactamase CHE-1.
[So] Source:Antimicrob Agents Chemother;60(3):1747-50, 2016 Jan 04.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The chromosome-encoded class C ß-lactamase CHE-1 produced by Enterobacter cloacae exhibits a lower sensitivity to avibactam than the P99 enzyme from which it is derived by a 6-residue deletion in the H-10 helix. In the present study, we investigated the sensitivity of CHE-1 to two other ß-lactamase inhibitors: LK-157 (or Lek 157), a tricyclic ß-lactam, and BAL29880, a bridged monobactam. With both compounds, the second-order rate constants for inactivation were significantly lower for CHE-1, which can thus be considered an inactivator-resistant mutant of P99. However, the second-order rate constant for the inactivation by BAL29880 probably remains adequate for a rather rapid reaction with CHE-1 in the absence of protection by the substrate.
[Mh] Termos MeSH primário: Compostos Azabicíclicos/farmacologia
Carbapenêmicos/farmacologia
Enterobacter cloacae/efeitos dos fármacos
Monobactamas/farmacologia
Compostos de Fenilureia/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/genética
[Mh] Termos MeSH secundário: Enterobacter cloacae/enzimologia
Enterobacter cloacae/genética
beta-Lactamases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Azabicyclo Compounds); 0 (BAL29880); 0 (Carbapenems); 0 (LK-157); 0 (Monobactams); 0 (Phenylurea Compounds); 0 (beta-Lactamase Inhibitors); 7352665165 (avibactam); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160106
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.02062-15


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[PMID]:26055384
[Au] Autor:Nicoletti AG; Marcondes MF; Martins WM; Almeida LG; Nicolás MF; Vasconcelos AT; Oliveira V; Gales AC
[Ad] Endereço:Laboratório Alerta, Disciplina de Infectologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil adrianagn@gmail.com.
[Ti] Título:Characterization of BKC-1 class A carbapenemase from Klebsiella pneumoniae clinical isolates in Brazil.
[So] Source:Antimicrob Agents Chemother;59(9):5159-64, 2015 Sep.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Three Klebsiella pneumoniae clinical isolates demonstrating carbapenem resistance were recovered from different patients hospitalized at two medical centers in São Paulo, Brazil. Resistance to all ß-lactams, quinolones, and some aminoglycosides was observed for these isolates that were susceptible to polymyxin B. Carbapenem hydrolysis, which was inhibited by clavulanic acid, was observed for all K. pneumoniae isolates that belonged to the same pulsed-field gel electrophoresis (PFGE) type and a novel sequence type (ST), ST1781 (clonal complex 442 [CC442]). A 10-kb nonconjugative incompatibility group Q (IncQ) plasmid, denominated p60136, was transferred to Escherichia coli strain TOP10 cells by electroporation. The full sequencing of p60136 showed that it was composed of a mobilization system, ISKpn23, the phosphotransferase aph3A-VI, and a 941-bp open reading frame (ORF) that codified a 313-amino acid protein. This ORF was named bla BKC-1. Brazilian Klebsiella carbapenemase-1 (BKC-1) showed a pI of 6.0 and possessed the highest identity (63%) with a ß-lactamase of Sinorhizobium meliloti, an environmental bacterium. Hydrolysis studies demonstrated that purified BKC-1 not only hydrolyzed carbapenems but also penicillins, cephalosporins, and monobactams. However, the carbapenems were less efficiently hydrolyzed due to their very low kcat values (0.0016 to 0.031 s(-1)). In fact, oxacillin was the best substrate for BKC-1 (kcat /Km , 53,522.6 mM(-1) s(-1)). Here, we report a new class A carbapenemase, confirming the diversity and rapid evolution of ß-lactamases in K. pneumoniae clinical isolates.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Klebsiella pneumoniae/enzimologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/metabolismo
Antibacterianos/farmacologia
Brasil
Carbapenêmicos/metabolismo
Carbapenêmicos/farmacologia
Cefalosporinas/metabolismo
Cefalosporinas/farmacologia
Farmacorresistência Bacteriana
Eletroforese em Gel de Campo Pulsado
Testes de Sensibilidade Microbiana
Monobactamas/metabolismo
Monobactamas/farmacologia
Penicilinas/metabolismo
Penicilinas/farmacologia
Sinorhizobium meliloti/efeitos dos fármacos
Sinorhizobium meliloti/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Carbapenems); 0 (Cephalosporins); 0 (Monobactams); 0 (Penicillins); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (carbapenemase)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:160301
[Lr] Data última revisão:
160301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150610
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00158-15



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