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  1 / 2516 MEDLINE  
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[PMID]:29353720
[Au] Autor:Liu S; Jing L; Yu ZJ; Wu C; Zheng Y; Zhang E; Chen Q; Yu Y; Guo L; Wu Y; Li GB
[Ad] Endereço:Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
[Ti] Título:((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-ß-lactamase inhibitors: Synthesis, kinetic and crystallographic studies.
[So] Source:Eur J Med Chem;145:649-660, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The emergence and global spread of metallo-ß-lactamase (MBL) mediated resistance to almost all ß-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Acetatos/síntese química
Acetatos/química
Animais
Sobrevivência Celular/efeitos dos fármacos
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Cinética
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Peixe-Zebra
Inibidores de beta-Lactamases/síntese química
Inibidores de beta-Lactamases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (beta-Lactamase Inhibitors); EC 3.5.2.- (VIM-2 beta-lactamase); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (beta-lactamase NDM-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


  2 / 2516 MEDLINE  
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[PMID]:29348071
[Au] Autor:Akhter S; Lund BA; Ismael A; Langer M; Isaksson J; Christopeit T; Leiros HS; Bayer A
[Ad] Endereço:Department of Chemistry, Faculty of Science and Technology, UiT- The Arctic University of Norway, N-9037 Tromsø, Norway.
[Ti] Título:A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design.
[So] Source:Eur J Med Chem;145:634-648, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:ß-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of ß-lactam resistance. The most prevalent resistance mechanism to ß-lactam antibiotics is expression of ß-lactamase enzymes. One way to overcome resistance caused by ß-lactamases, is the development of ß-lactamase inhibitors and today several ß-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R or R binders by their overall binding conformation in relation to the binding of the R and R side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC = 2.9 µM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.
[Mh] Termos MeSH primário: Desenho de Drogas
Resistência Microbiana a Medicamentos/efeitos dos fármacos
Bibliotecas de Moléculas Pequenas/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Escherichia coli/enzimologia
Klebsiella pneumoniae/enzimologia
Estrutura Molecular
Bibliotecas de Moléculas Pequenas/síntese química
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
Inibidores de beta-Lactamases/síntese química
Inibidores de beta-Lactamases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Small Molecule Libraries); 0 (beta-Lactamase Inhibitors); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (oxacillinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE


  3 / 2516 MEDLINE  
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[PMID]:29298507
[Au] Autor:Gavriel H; Jabarin B; Israel O; Eviatar E
[Ad] Endereço:1 Department of Otolaryngology Head and Neck Surgery, Assaf Harofeh Medical Center, Zerifin, Israel.
[Ti] Título:Conservative Management for Subperiosteal Orbital Abscess in Adults: A 20-Year Experience.
[So] Source:Ann Otol Rhinol Laryngol;127(3):162-166, 2018 Mar.
[Is] ISSN:1943-572X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Orbital complications (OC) secondary to acute rhinosinusitis (ARS) in adults are less common than in children, with assumed worse outcome. MATERIALS AND METHODS: Adults with OC secondary to ARS between 1994 and 2014 were reviewed retrospectively. Parameters recorded included age, gender, clinical symptoms and signs, computed tomography (CT) scan findings, duration of hospitalization, treatment before and during admission, cultures, and outcome. RESULTS: Thirty-seven adults with a mean age of 34.6 years, 27 males and 10 females, were diagnosed with OC, 19 (51.3%) with subperiosteal orbital abscess (SPOA), and none with orbital abscess/cellulitis or cavernous sinus thrombosis. Twelve patients with SPOA were managed conservatively with Amoxicillin-Clavulanate in most cases, and only 7 (36.8%) underwent surgery. A CT scan was performed in 27 cases revealing rhinosinusitis in all patients, including frontal involvement in 19 (51.3%) patients and sphenoid sinus in 16 (43.2%). CONCLUSIONS: A shift toward conservative treatment in cases of SPOA has long been integrated in the management protocols, mainly in children under 9 years old. The presumed worse prognosis in adults is not supported in our study, and a conservative treatment is urged to be considered in this group of patients albeit the more extensive radiologic involvement of their sinuses.
[Mh] Termos MeSH primário: Abscesso
Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem
Celulite Orbitária
Rinite/complicações
Sinusite/complicações
[Mh] Termos MeSH secundário: Abscesso/diagnóstico
Abscesso/etiologia
Abscesso/terapia
Doença Aguda
Adulto
Tratamento Conservador/métodos
Drenagem/métodos
Feminino
Seres Humanos
Israel/epidemiologia
Masculino
Órbita/diagnóstico por imagem
Celulite Orbitária/diagnóstico
Celulite Orbitária/etiologia
Celulite Orbitária/terapia
Prognóstico
Estudos Retrospectivos
Tomografia Computadorizada por Raios X/métodos
Resultado do Tratamento
Inibidores de beta-Lactamases/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (beta-Lactamase Inhibitors); 74469-00-4 (Amoxicillin-Potassium Clavulanate Combination)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180105
[St] Status:MEDLINE
[do] DOI:10.1177/0003489417751155


  4 / 2516 MEDLINE  
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[PMID]:29248295
[Au] Autor:Zhang E; Wang MM; Huang SC; Xu SM; Cui DY; Bo YL; Bai PY; Hua YG; Xiao CL; Qin S
[Ad] Endereço:School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Pr
[Ti] Título:NOTA analogue: A first dithiocarbamate inhibitor of metallo-ß-lactamases.
[So] Source:Bioorg Med Chem Lett;28(2):214-221, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the ß-lactam antibiotics, the metallo-ß-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of bla . The compound 5 was non-hemolytic, even at a concentration of 1000 µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63 ±â€¯1.27 µM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Compostos Heterocíclicos/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Sobrevivência Celular/efeitos dos fármacos
Citrobacter freundii/efeitos dos fármacos
Relação Dose-Resposta a Droga
Escherichia coli/efeitos dos fármacos
Células HeLa
Compostos Heterocíclicos/síntese química
Compostos Heterocíclicos/química
Seres Humanos
Klebsiella pneumoniae/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Proteus mirabilis/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores de beta-Lactamases/síntese química
Inibidores de beta-Lactamases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Heterocyclic Compounds); 0 (beta-Lactamase Inhibitors); 56491-86-2 (1,4,7-triazacyclononane-N,N',N''-triacetic acid); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  5 / 2516 MEDLINE  
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[PMID]:28809565
[Au] Autor:Chen AY; Thomas PW; Stewart AC; Bergstrom A; Cheng Z; Miller C; Bethel CR; Marshall SH; Credille CV; Riley CL; Page RC; Bonomo RA; Crowder MW; Tierney DL; Fast W; Cohen SM
[Ad] Endereço:Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
[Ti] Título:Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-ß-lactamase-1.
[So] Source:J Med Chem;60(17):7267-7283, 2017 Sep 14.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The efficacy of ß-lactam antibiotics is threatened by the emergence and global spread of metallo-ß-lactamase (MBL) mediated resistance, specifically New Delhi metallo-ß-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related ß-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.
[Mh] Termos MeSH primário: Escherichia coli/enzimologia
Klebsiella pneumoniae/enzimologia
Ácidos Picolínicos/química
Ácidos Picolínicos/farmacologia
Inibidores de beta-Lactamases/química
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/farmacologia
Escherichia coli/efeitos dos fármacos
Infecções por Escherichia coli/tratamento farmacológico
Infecções por Escherichia coli/microbiologia
Seres Humanos
Infecções por Klebsiella/tratamento farmacológico
Infecções por Klebsiella/microbiologia
Klebsiella pneumoniae/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Picolinic Acids); 0 (beta-Lactamase Inhibitors); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (beta-lactamase NDM-1); UE81S5CQ0G (dipicolinic acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00407


  6 / 2516 MEDLINE  
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[PMID]:28784300
[Au] Autor:Zhang J; Wang S; Wei Q; Guo Q; Bai Y; Yang S; Song F; Zhang L; Lei X
[Ad] Endereço:Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for
[Ti] Título:Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance.
[So] Source:Bioorg Med Chem;25(19):5133-5141, 2017 Oct 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The ß-lactam antibiotic resistance of Gram-negative bacteria has shown to be a critical global health problem. One of the primary reasons for the drug resistance is the existence of ß-lactamases especially metallo-ß-lactamases such as New Delhi metallo-ß-lactamase (NDM-1) and Verona Integron-encoded metallo-ß-lactamase (VIM-2). The fungal natural product Aspergillomarasmine A (AMA) has proven to be a promising inhibitor of NDM-1 and VIM-2 both in vitro and in vivo. Seven new analogues of AMA were synthesized by utilizing different strategies. The biological evaluation of these analogues was performed to study the structure-activity relationship of AMA both in vitro and in vivo. Remarkably, the lead compound 4 showed synergistic effect in combination with Meropenem to overcome the antibiotic resistance of the Gram-negative bacteria such as K. pneumoniae (BAA-2146) expressing NDM-1.
[Mh] Termos MeSH primário: Ácido Aspártico/análogos & derivados
Klebsiella pneumoniae/efeitos dos fármacos
Klebsiella pneumoniae/enzimologia
Inibidores de beta-Lactamases/química
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Ácido Aspártico/síntese química
Ácido Aspártico/química
Ácido Aspártico/farmacologia
Seres Humanos
Infecções por Klebsiella/tratamento farmacológico
Infecções por Klebsiella/microbiologia
Resistência beta-Lactâmica/efeitos dos fármacos
Inibidores de beta-Lactamases/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (beta-Lactamase Inhibitors); 30KYC7MIAI (Aspartic Acid); 3484-65-9 (aspergillomarasmine A); EC 3.5.2.6 (beta-Lactamases); EC 3.5.2.6 (beta-lactamase NDM-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


  7 / 2516 MEDLINE  
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[PMID]:28767588
[Au] Autor:Gugliandolo A; Caio C; Mezzatesta ML; Rifici C; Bramanti P; Stefani S; Mazzon E
[Ad] Endereço:aIRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Messina bSection of Microbiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
[Ti] Título:Successful ceftazidime-avibactam treatment of MDR-KPC-positive Klebsiella pneumoniae infection in a patient with traumatic brain injury: A case report.
[So] Source:Medicine (Baltimore);96(31):e7664, 2017 Aug.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Carbapenem-resistant Enterobacteriaceae infections are a serious health care problem, because of the high mortality. Carbapenem resistance is mainly caused by carbapenemases production, including Klebsiella pneumoniae carbapenemase (KPC). Ceftazidime-avibactam is a new cephalosporin/ß-lactamase inhibitor combination for the treatment of complicated urinary, intra-abdominal infections, and nosocomial pneumonia caused by gram negative, or other serious gram-negative infections. PATIENT CONCERNS: We showed the case of a 27-year-old patient, hospitalized for traumatic brain injury and chest trauma, with KPC-producing Klebsiella pneumoniae infection. DIAGNOSES: Blood and bronchial aspirate culture analysis detected an infection caused by MDR Klebsiella pneumoniae, resistant to meropenem, ertapenem, piperacillin/tazobactam, amoxicillin/clavulanic acid, aztreonam, ceftazidime, cefotaxime, cefepime, amikacin, ciprofloxacin, trimethoprim/sulfamethoxazole, colistin while it showed an intermediate sensitivity to gentamicin and was sensitive to ceftazidime-avibactam. Molecular analyses revealed that the isolate belonged to the epidemic clone sequence type 258 (ST258) carrying blaKPC-3, blaTEM-1, and blaSHV-11genes. INTERVENTIONS: After various combined antibiotic therapies without improvements, he was treated with ceftazidime-avibactam, on a compassionate-use basis. OUTCOMES: With ceftazidime-avibactam monotherapy clinical and microbiological clearance was obtained. A week after the end of the therapy microbiological analysis was repeated and a positive rectal swab for KPC-Klebsiella pneumoniae was found, becoming negative after 1 month. Moreover, the patient did not show any relapses for up to 18 weeks. LESSONS: This case indicates that ceftazidime-avibactam monotherapy could be efficacious against KPC positive Klebsiella pneumoniae infections.
[Mh] Termos MeSH primário: Compostos Azabicíclicos/uso terapêutico
Lesões Encefálicas Traumáticas/complicações
Ceftazidima/uso terapêutico
Infecções por Klebsiella/tratamento farmacológico
Klebsiella pneumoniae
Inibidores de beta-Lactamases/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Lesões Encefálicas Traumáticas/microbiologia
Ensaios de Uso Compassivo
Estado Terminal
Farmacorresistência Bacteriana Múltipla
Seres Humanos
Infecções por Klebsiella/complicações
Klebsiella pneumoniae/efeitos dos fármacos
Klebsiella pneumoniae/genética
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azabicyclo Compounds); 0 (avibactam, ceftazidime drug combination); 0 (beta-Lactamase Inhibitors); 9M416Z9QNR (Ceftazidime)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007664


  8 / 2516 MEDLINE  
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[PMID]:28592240
[Au] Autor:Seo YB; Lee J; Kim YK; Lee SS; Lee JA; Kim HY; Uh Y; Kim HS; Song W
[Ad] Endereço:Division of Infectious Diseases, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
[Ti] Título:Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli.
[So] Source:BMC Infect Dis;17(1):404, 2017 Jun 07.
[Is] ISSN:1471-2334
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the therapeutic efficacy of piperacillin-tazobactam (PTZ), cefepime, and ertapenem in febrile nosocomial urinary tract infection with ESBL-producing Escherichia coli (ESBL-EC). METHODS: This study was conducted at three university hospitals between January 2013 and August 2015. Hospitalized adult patients presenting with fever were screened for healthcare-associated urinary tract infection (HA-UTI). When ESBL-EC was solely detected and susceptible to a randomized antibiotic in vitro, the case was included in the final analysis. Participants were treated for 10-14 days with PTZ, cefepime, or ertapenem. RESULTS: A total of 66 participants were evenly assigned to the PTZ and ertapenem treatment groups. After the recruitment of six participants, assignment to the cefepime treatment group was stopped because of an unexpectedly high treatment failure rate. The baseline characteristics of these participants did not differ from participants in other treatment groups. The clinical and microbiological response to PTZ treatment was estimated to be 94% and was similar to the response to ertapenem treatment. The efficacy of cefepime was 33.3%. In the cefepime group, age, Charlson comorbidity index, genotype, and minimal inhibitory concentration (MIC) did not significantly affect the success of treatment. Similarly, genotype seemed to be irrelevant with respect to clinical outcome in the PTZ group. Expired cases tended to involve septic shock with a high Charlson comorbidity index and high MIC. CONCLUSION: Results from this study suggest that PTZ is effective in the treatment of urinary tract infection caused by ESBL-EC when the in vitro test indicates susceptibility. In addition, cefepime should not be used as an alternative treatment for urinary tract infection caused by ESBL-EC. TRIAL REGISTRATION: The trial was registered with the Clinical Research Information Service of Korea Centers for Disease Control and Prevention. (KCT0001895).
[Mh] Termos MeSH primário: Antibacterianos/uso terapêutico
Infecções por Escherichia coli/tratamento farmacológico
Escherichia coli/efeitos dos fármacos
Ácido Penicilânico/análogos & derivados
Infecções Urinárias/tratamento farmacológico
Inibidores de beta-Lactamases/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Cefalosporinas/uso terapêutico
Infecção Hospitalar
Escherichia coli/enzimologia
Escherichia coli/genética
Escherichia coli/isolamento & purificação
Infecções por Escherichia coli/microbiologia
Feminino
Genótipo
Seres Humanos
Masculino
Meia-Idade
Ácido Penicilânico/uso terapêutico
Piperacilina/uso terapêutico
Estudos Prospectivos
República da Coreia
Infecções Urinárias/microbiologia
beta-Lactamases/genética
beta-Lactamas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Cephalosporins); 0 (beta-Lactamase Inhibitors); 0 (beta-Lactams); 157044-21-8 (piperacillin, tazobactam drug combination); 807PW4VQE3 (cefepime); 87-53-6 (Penicillanic Acid); EC 3.5.2.6 (beta-Lactamases); G32F6EID2H (ertapenem); SE10G96M8W (tazobactam); X00B0D5O0E (Piperacillin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1186/s12879-017-2502-x


  9 / 2516 MEDLINE  
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[PMID]:28505394
[Au] Autor:Sevaille L; Gavara L; Bebrone C; De Luca F; Nauton L; Achard M; Mercuri P; Tanfoni S; Borgianni L; Guyon C; Lonjon P; Turan-Zitouni G; Dzieciolowski J; Becker K; Bénard L; Condon C; Maillard L; Martinez J; Frère JM; Dideberg O; Galleni M; Docquier JD; Hernandez JF
[Ad] Endereço:Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.
[Ti] Título:1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-ß-lactamases.
[So] Source:ChemMedChem;12(12):972-985, 2017 Jun 21.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Metallo-ß-lactamases (MBLs) cause resistance of Gram-negative bacteria to ß-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC values toward plasmodial glyoxalase II were in the 10 µm range.
[Mh] Termos MeSH primário: Tionas/farmacologia
Triazóis/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Aeromonas hydrophila/enzimologia
Relação Dose-Resposta a Droga
Estrutura Molecular
Stenotrophomonas maltophilia/enzimologia
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
Triazóis/síntese química
Triazóis/química
Inibidores de beta-Lactamases/síntese química
Inibidores de beta-Lactamases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Thiones); 0 (Triazoles); 0 (beta-Lactamase Inhibitors); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700186


  10 / 2516 MEDLINE  
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[PMID]:28504895
[Au] Autor:McGeary RP; Tan DT; Schenk G
[Ad] Endereço:School of Chemistry & Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia.
[Ti] Título:Progress toward inhibitors of metallo-ß-lactamases.
[So] Source:Future Med Chem;9(7):673-691, 2017 May.
[Is] ISSN:1756-8927
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The global overuse of antibiotics has led to the emergence of drug-resistant pathogenic bacteria. Bacteria can combat ß-lactams by expressing ß-lactamases. Inhibitors of one class of ß-lactamase, the serine-ß-lactamases, are used clinically to prevent degradation of ß-lactam antibiotics. However, a second class of ß-lactamase, the metallo-ß-lactamases (MBLs), function by a different mechanism to serine-ß-lactamases and no inhibitors of MBLs have progressed to be used in the clinic. Bacteria that express MBLs are an increasingly important threat to human health. This review outlines various approaches taken to discover MBL inhibitors, with an emphasis on the different chemical classes of inhibitors. Recent progress, particularly new screening methods and the rational design of potent MBL inhibitors are discussed.
[Mh] Termos MeSH primário: Antibacterianos/química
Antibacterianos/farmacologia
Inibidores de beta-Lactamases/química
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Animais
Antibacterianos/metabolismo
Antibacterianos/uso terapêutico
Bactérias/efeitos dos fármacos
Bactérias/metabolismo
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
Resistência beta-Lactâmica
Inibidores de beta-Lactamases/metabolismo
Inibidores de beta-Lactamases/uso terapêutico
beta-Lactamas/metabolismo
beta-Lactamas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (beta-Lactamase Inhibitors); 0 (beta-Lactams); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.4155/fmc-2017-0007



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