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Pesquisa : D02.540.576.500.992.445 [Categoria DeCS]
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[PMID]:28711353
[Au] Autor:Jia L; Yan M; Shen Y; Qin Y; Qiang S; Ma S
[Ad] Endereço:Department of Medicinal Chemistry Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences, Shandong University, a. 44 West Culture Road, Jinan 250012 PR China.
[Ti] Título:Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides.
[So] Source:Bioorg Med Chem Lett;27(16):3693-3697, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5µg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125-1µg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.
[Mh] Termos MeSH primário: Antibacterianos/síntese química
Claritromicina/síntese química
Cetolídeos/química
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/farmacologia
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Claritromicina/análogos & derivados
Claritromicina/farmacologia
Farmacorresistência Bacteriana/efeitos dos fármacos
Eritromicina/farmacologia
Bactérias Gram-Negativas/efeitos dos fármacos
Bactérias Gram-Positivas/efeitos dos fármacos
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Metiltransferases/genética
Metiltransferases/metabolismo
Testes de Sensibilidade Microbiana
Streptococcus pneumoniae/efeitos dos fármacos
Streptococcus pyogenes/efeitos dos fármacos
Relação Estrutura-Atividade
[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 (Ketolides); 0 (MefA protein, Streptococcus); 0 (Membrane Proteins); 63937KV33D (Erythromycin); EC 2.1.1.- (Methyltransferases); EC 2.1.1.184 (ErmA protein, Bacteria); H1250JIK0A (Clarithromycin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


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[PMID]:28419786
[Au] Autor:Pavlova A; Parks JM; Oyelere AK; Gumbart JC
[Ad] Endereço:School of Physics, Georgia Institute of Technology, Atlanta, GA, USA.
[Ti] Título:Toward the rational design of macrolide antibiotics to combat resistance.
[So] Source:Chem Biol Drug Des;90(5):641-652, 2017 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.
[Mh] Termos MeSH primário: Antibacterianos/química
Antibacterianos/farmacologia
Desenho de Drogas
Escherichia coli/efeitos dos fármacos
Macrolídeos/química
Macrolídeos/farmacologia
[Mh] Termos MeSH secundário: Azitromicina/análogos & derivados
Azitromicina/química
Azitromicina/farmacologia
Farmacorresistência Bacteriana
Eritromicina/química
Eritromicina/farmacologia
Escherichia coli/genética
Infecções por Escherichia coli/tratamento farmacológico
Infecções por Escherichia coli/microbiologia
Seres Humanos
Cetolídeos/química
Cetolídeos/farmacologia
Simulação de Dinâmica Molecular
Mutação Puntual/efeitos dos fármacos
Ribossomos/efeitos dos fármacos
Ribossomos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Ketolides); 0 (Macrolides); 63937KV33D (Erythromycin); 83905-01-5 (Azithromycin); KI8H7H19WL (telithromycin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.13004


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[PMID]:28302508
[Au] Autor:Anwar HF; Andrei M; Undheim K
[Ad] Endereço:C10 Pharma AS, Oslo, Norway.
[Ti] Título:Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group.
[So] Source:Bioorg Med Chem;25(8):2313-2326, 2017 Apr 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O -methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,ß-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus.
[Mh] Termos MeSH primário: Antibacterianos/síntese química
Claritromicina/síntese química
Cetolídeos/síntese química
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/farmacologia
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13
Claritromicina/química
Claritromicina/farmacologia
Cetolídeos/química
Testes de Sensibilidade Microbiana
Espectroscopia de Prótons por Ressonância Magnética
Espectrometria de Massas por Ionização por Electrospray
Staphylococcus aureus/efeitos dos fármacos
Streptococcus pneumoniae/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Ketolides); H1250JIK0A (Clarithromycin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28256375
[Au] Autor:Tian JC; Han X; Lv W; Li YX; Wang H; Fan BZ; Cushman M; Liang JH
[Ad] Endereço:School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
[Ti] Título:Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides.
[So] Source:Bioorg Med Chem Lett;27(7):1513-1524, 2017 04 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Cetolídeos/farmacologia
Oximas/farmacologia
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Bactérias Gram-Negativas/efeitos dos fármacos
Bactérias Gram-Positivas/efeitos dos fármacos
Cetolídeos/síntese química
Cetolídeos/química
Simulação de Acoplamento Molecular
Oximas/síntese química
Oximas/química
Ribossomos/química
Estereoisomerismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Ketolides); 0 (Oximes)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE


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[PMID]:27864779
[Au] Autor:Woo SG; Lee SY; Lee SM; Lim KH; Ha EJ; Eom YB
[Ad] Endereço:Department of Medical Science, College of Medical Sciences, Soonchunhyang University, 22 Soonchunhyang-ro, Shinchang-myeon, Asan-si, Chungcheongnam-do, 31538, Republic of Korea.
[Ti] Título:Activity of novel inhibitors of Staphylococcus aureus biofilms.
[So] Source:Folia Microbiol (Praha);62(2):157-167, 2017 Mar.
[Is] ISSN:1874-9356
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Staphylococcus aureus is one of the most important pathogens causing chronic biofilm infections. These are becoming more difficult to treat owing to drug resistance, particularly because S. aureus biofilms limit the efficacy of antimicrobial agents, leading to high morbidity and mortality. In the present study, we screened for inhibitors of S. aureus biofilm formation using a natural product library from the Korea Chemical Bank (KCB). Screening by crystal violet-based biomass staining assay identified hit compounds. Further examination of antibiofilm properties of these compounds was conducted and led to the identification of celastrol and telithromycin. In vitro, both celastrol and telithromycin were toxic to planktonic S. aureus and also active against a clinical methicillin-resistant S. aureus (MRSA) isolate. The effect of the compounds on preformed biofilms of clinical MRSA isolates was evaluated by confocal laser scanning microscopy (CLSM), which revealed the absence of typical biofilm architecture. In addition, celastrol and telithromycin inhibited the production of extracellular protein at selected sub-MIC concentrations, which revealed the reduced extracellular polymeric substance (EPS) secretion. Celastrol exhibited greater cytotoxicity than telithromycin. These data suggest that the hit compounds, especially telithromycin, could be considered novel inhibitors of S. aureus biofilm. Although the mechanisms of the effects on S. aureus biofilms are not fully understood, our data suggest that telithromycin could be a useful adjuvant therapeutic agent for S. aureus biofilm-related infections.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Biofilmes/efeitos dos fármacos
Cetolídeos/farmacologia
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
Staphylococcus aureus/efeitos dos fármacos
Triterpenos/farmacologia
[Mh] Termos MeSH secundário: Biofilmes/crescimento & desenvolvimento
Produtos Biológicos/farmacologia
Violeta de Genciana
Ensaios de Triagem em Larga Escala
Staphylococcus aureus Resistente à Meticilina/fisiologia
Testes de Sensibilidade Microbiana
Plâncton/efeitos dos fármacos
Plâncton/crescimento & desenvolvimento
Bibliotecas de Moléculas Pequenas/farmacologia
Staphylococcus aureus/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Biological Products); 0 (Ketolides); 0 (Small Molecule Libraries); 0 (Triterpenes); J4Z741D6O5 (Gentian Violet); KI8H7H19WL (telithromycin); L8GG98663L (tripterine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161120
[St] Status:MEDLINE
[do] DOI:10.1007/s12223-016-0485-4


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[PMID]:27401563
[Au] Autor:Figueira M; Fernandes P; Pelton SI
[Ad] Endereço:Section of Pediatric Infectious Diseases, Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston, Massachusetts, USA.
[Ti] Título:Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae.
[So] Source:Antimicrob Agents Chemother;60(9):5533-8, 2016 Sep.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Solithromycin (CEM-101) is a "fourth-generation" macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistant Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains of S. pneumoniae or NTHi. Plasma PK (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted in Cmax and AUC0-24 values of 2.2 µg/ml and 27.4 µg · h/ml in plasma and 1.7 µg/ml and 28.2 µg · h/ml in extracellular MEF on day 1. By day 3, Cmax and AUC0-24 values had increased to 4.5 µg/ml and 54 µg · h/ml in plasma and 4.8 µg/ml and 98.6 µg · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 µg/ml (isolate BCH1), 2/2 µg/ml (isolate BMC1247C), and 4/4 µg/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. For S. pneumoniae EOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 µg/ml (S. pneumoniae 331), 0.125/1 µg/ml (S. pneumoniae CP-645 [MLSB phenotype]), and 0.5/2 µg/ml (CP-712 [mefA subclass mefA resistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected with S. pneumoniae 331 and S. pneumoniae CP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of ≤2 µg/ml and 100% of ME infected with S. pneumoniae with an MIC of ≤0.125 µg/ml.
[Mh] Termos MeSH primário: Infecções por Haemophilus/tratamento farmacológico
Haemophilus influenzae/efeitos dos fármacos
Macrolídeos/farmacologia
Macrolídeos/uso terapêutico
Otite Média/tratamento farmacológico
Infecções Pneumocócicas/tratamento farmacológico
Streptococcus pneumoniae/efeitos dos fármacos
Triazóis/farmacologia
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Antibacterianos/farmacologia
Antibacterianos/uso terapêutico
Pré-Escolar
Chinchila
Orelha Média/microbiologia
Orelha Média/virologia
Feminino
Seres Humanos
Lactente
Cetolídeos/farmacologia
Cetolídeos/uso terapêutico
Masculino
Testes de Sensibilidade Microbiana
Otite Média/microbiologia
Otite Média/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Ketolides); 0 (Macrolides); 0 (Triazoles); 9U1ETH79CK (solithromycin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160713
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00863-16


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[PMID]:27353268
[Au] Autor:Cipcic Paljetak H; Verbanac D; Padovan J; Dominis-Kramaric M; Kelneric Z; Peric M; Banjanac M; Ergovic G; Simon N; Broskey J; Holmes DJ; Erakovic Haber V
[Ad] Endereço:GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia hana.paljetak@mef.hr.
[Ti] Título:Macrolones Are a Novel Class of Macrolide Antibiotics Active against Key Resistant Respiratory Pathogens In Vitro and In Vivo.
[So] Source:Antimicrob Agents Chemother;60(9):5337-48, 2016 Sep.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Farmacorresistência Bacteriana/efeitos dos fármacos
Macrolídeos/farmacologia
Pneumonia Pneumocócica/tratamento farmacológico
Inibidores da Síntese de Proteínas/farmacologia
Streptococcus pneumoniae/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antibacterianos/farmacocinética
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Modelos Animais de Doenças
Farmacorresistência Bacteriana/genética
Escherichia coli/química
Haemophilus influenzae/efeitos dos fármacos
Haemophilus influenzae/crescimento & desenvolvimento
Cetolídeos/farmacologia
Lincosamidas/farmacologia
Macrolídeos/farmacocinética
Masculino
Metiltransferases/genética
Metiltransferases/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Pneumonia Pneumocócica/microbiologia
Biossíntese de Proteínas/efeitos dos fármacos
Inibidores da Síntese de Proteínas/farmacocinética
Staphylococcus aureus/efeitos dos fármacos
Staphylococcus aureus/crescimento & desenvolvimento
Streptococcus pneumoniae/genética
Streptococcus pneumoniae/crescimento & desenvolvimento
Streptococcus pyogenes/efeitos dos fármacos
Streptococcus pyogenes/crescimento & desenvolvimento
Estreptogramina B/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Ketolides); 0 (Lincosamides); 0 (Macrolides); 0 (Protein Synthesis Inhibitors); 3131-03-1 (Streptogramin B); EC 2.1.1.- (Methyltransferases); EC 2.1.1.184 (ErmA protein, Bacteria); KI8H7H19WL (telithromycin)
[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:160630
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00524-16


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[PMID]:27193679
[Au] Autor:Seiple IB; Zhang Z; Jakubec P; Langlois-Mercier A; Wright PM; Hog DT; Yabu K; Allu SR; Fukuzaki T; Carlsen PN; Kitamura Y; Zhou X; Condakes ML; Szczypinski FT; Green WD; Myers AG
[Ad] Endereço:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
[Ti] Título:A platform for the discovery of new macrolide antibiotics.
[So] Source:Nature;533(7603):338-45, 2016 05 19.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.
[Mh] Termos MeSH primário: Antibacterianos/síntese química
Antibacterianos/farmacologia
Descoberta de Drogas/métodos
Macrolídeos/síntese química
Macrolídeos/farmacologia
[Mh] Termos MeSH secundário: Amino Açúcares/síntese química
Amino Açúcares/química
Amino Açúcares/farmacologia
Antibacterianos/química
Bactérias/efeitos dos fármacos
Seres Humanos
Cetolídeos/síntese química
Cetolídeos/química
Macrolídeos/química
Testes de Sensibilidade Microbiana
Estrutura Molecular
Bibliotecas de Moléculas Pequenas/síntese química
Bibliotecas de Moléculas Pequenas/química
Triazóis/síntese química
Triazóis/química
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Sugars); 0 (Anti-Bacterial Agents); 0 (Ketolides); 0 (Macrolides); 0 (Small Molecule Libraries); 0 (Triazoles); 9U1ETH79CK (solithromycin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160520
[St] Status:MEDLINE
[do] DOI:10.1038/nature17967


  9 / 780 MEDLINE  
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[PMID]:27118243
[Au] Autor:Zheng Z; Du D; Cao L; Liu J; Chen X
[Ad] Endereço:Shandong Xinhua Pharmaceutical Co., Ltd, Zibo City, Shandong Province, China.
[Ti] Título:Synthesis and antibacterial activity of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives.
[So] Source:J Antibiot (Tokyo);69(11):811-817, 2016 Nov.
[Is] ISSN:0021-8820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives (6a-h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus (MIC =0.031-2 µg ml ) except 6g and Methicillin-sensitive S. epidermidis (MIC =0.031-0.5 µg ml ). MIC of 6d against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular, compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus.
[Mh] Termos MeSH primário: Antibacterianos/síntese química
Antibacterianos/farmacologia
Carbamatos/química
Carbamatos/farmacologia
Eritromicina/análogos & derivados
[Mh] Termos MeSH secundário: Azitromicina/farmacologia
Eritromicina/síntese química
Eritromicina/farmacologia
Haemophilus influenzae/efeitos dos fármacos
Cetolídeos/farmacologia
Resistência a Meticilina
Testes de Sensibilidade Microbiana
Staphylococcus aureus/efeitos dos fármacos
Staphylococcus epidermidis/efeitos dos fármacos
Streptococcus pneumoniae/efeitos dos fármacos
Streptococcus pyogenes/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-(3-((3-methylphenylcarbamoyl)oxy)propylamino)-3-oxoerythromycin A 11-N,12-O-cyclic carbamate); 0 (11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-(3-((4-nitrophenylcarbamoyl)oxy)propylamino)-3-oxoerythromycin A 11-N,12-O-cyclic carbamate); 0 (Anti-Bacterial Agents); 0 (Carbamates); 0 (Ketolides); 63937KV33D (Erythromycin); 83905-01-5 (Azithromycin); J0086219X6 (cethromycin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160428
[St] Status:MEDLINE
[do] DOI:10.1038/ja.2016.42


  10 / 780 MEDLINE  
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[PMID]:27044551
[Au] Autor:Farrell DJ; Flamm RK; Sader HS; Jones RN
[Ad] Endereço:JMI Laboratories, North Liberty, Iowa, USA david-farrell@jmilabs.com.
[Ti] Título:Results from the Solithromycin International Surveillance Program (2014).
[So] Source:Antimicrob Agents Chemother;60(6):3662-8, 2016 Jun.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 µg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 µg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 µg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 µg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 µg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 µg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 µg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 µg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 µg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 µg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 µg/ml), and all isolates were inhibited at MIC values of ≤0.5 µg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Infecções Bacterianas/epidemiologia
Infecções Comunitárias Adquiridas/epidemiologia
Monitoramento Epidemiológico
Macrolídeos/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Ásia/epidemiologia
Azitromicina/farmacologia
Infecções Bacterianas/tratamento farmacológico
Infecções Bacterianas/microbiologia
Infecções Comunitárias Adquiridas/tratamento farmacológico
Infecções Comunitárias Adquiridas/microbiologia
Europa (Continente)/epidemiologia
Haemophilus influenzae/efeitos dos fármacos
Haemophilus influenzae/crescimento & desenvolvimento
Haemophilus influenzae/isolamento & purificação
Seres Humanos
Cooperação Internacional
Cetolídeos/farmacologia
América Latina/epidemiologia
Testes de Sensibilidade Microbiana
Moraxella (Branhamella) catarrhalis/efeitos dos fármacos
Moraxella (Branhamella) catarrhalis/crescimento & desenvolvimento
Moraxella (Branhamella) catarrhalis/isolamento & purificação
Staphylococcus aureus/efeitos dos fármacos
Staphylococcus aureus/crescimento & desenvolvimento
Staphylococcus aureus/isolamento & purificação
Streptococcus/efeitos dos fármacos
Streptococcus/crescimento & desenvolvimento
Streptococcus/isolamento & purificação
Streptococcus pneumoniae/efeitos dos fármacos
Streptococcus pneumoniae/crescimento & desenvolvimento
Streptococcus pneumoniae/isolamento & purificação
Estados Unidos/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Ketolides); 0 (Macrolides); 0 (Triazoles); 83905-01-5 (Azithromycin); 9U1ETH79CK (solithromycin); KI8H7H19WL (telithromycin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160406
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.00185-16



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