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1.
J Chromatogr Sci ; 56(3): 285-291, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244148

RESUMO

A quantitative LC-MS/MS method has been developed for simultaneous determination of bacitracin A, bacitracin B, colistin A, colistin B and virginiamycin M1 in feed. This rapid simple and effective extraction method was based on matrix solid-phase dispersion. Qualitative and quantitative analyses were performed by LC-ESI-MS/MS. CCß of polypeptide antibiotics upon the method ranged from 9.6 to 15.8 µg kg-1 and 19.4 to 27.5 µg kg-1, respectively. The limit of quantification of polypeptide antibiotics was 25 µg kg-1 in feed samples. The recoveries of polypeptide antibiotics spiked in feed samples at a concentration range of 25-100 µg kg-1 were found above 75.9-87.9% with relative standard deviations within days less than 15.7% and between days less than 20.6%. This rapid and reliable method can be used to efficiently separate, characterize and quantify the residues of polypeptide antibiotics in feed with advantages of simple pretreatment and environmental friendly.


Assuntos
Ração Animal/análise , Bacitracina/análise , Colistina/análise , Resíduos de Drogas/análise , Extração em Fase Sólida/métodos , Virginiamicina/análise , Bacitracina/química , Bacitracina/isolamento & purificação , Cromatografia Líquida/métodos , Colistina/química , Colistina/isolamento & purificação , Resíduos de Drogas/química , Resíduos de Drogas/isolamento & purificação , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Virginiamicina/química , Virginiamicina/isolamento & purificação
2.
J Am Chem Soc ; 139(38): 13304-13307, 2017 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-28902996

RESUMO

Streptogramin antibiotics are used clinically to treat multidrug-resistant bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their utility. New methods to chemically modify streptogramins would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Here we report a modular, scalable synthesis of group A streptogramin antibiotics that proceeds in 6-8 linear steps from simple chemical building blocks. We have applied our route to the synthesis of four natural products in this class including two that have never before been accessed by fully synthetic routes. We anticipate that this work will lead to the discovery of new streptogramin antibiotics that overcome previous limitations of the class.


Assuntos
Antibacterianos/síntese química , Estreptogramina Grupo A/síntese química , Antibacterianos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estrutura Molecular , Estreptogramina Grupo A/química , Virginiamicina/síntese química , Virginiamicina/química
3.
J Am Chem Soc ; 138(12): 4155-67, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-26982529

RESUMO

Modular polyketide synthases (PKSs) direct the biosynthesis of clinically valuable secondary metabolites in bacteria. The fidelity of chain growth depends on specific recognition between successive subunits in each assembly line: interactions mediated by C- and N-terminal "docking domains" (DDs). We have identified a new family of DDs in trans-acyl transferase PKSs, exemplified by a matched pair from the virginiamycin (Vir) system. In the absence of C-terminal partner (VirA (C)DD) or a downstream catalytic domain, the N-terminal DD (VirFG (N)DD) exhibits multiple characteristics of an intrinsically disordered protein. Fusion of the two docking domains results in a stable fold for VirFG (N)DD and an overall protein-protein complex of unique topology whose structure we support by site-directed mutagenesis. Furthermore, using small-angle X-ray scattering (SAXS), the positions of the flanking acyl carrier protein and ketosynthase domains have been identified, allowing modeling of the complete intersubunit interface.


Assuntos
Aciltransferases/metabolismo , Policetídeo Sintases/metabolismo , Virginiamicina/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Virginiamicina/metabolismo
4.
J Anim Sci ; 92(3): 1144-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24492576

RESUMO

Dried distiller's grains (DG) produced from ethanol fermentations dosed with 0 (control), 2, or 20 mg/kg virginiamycin-based product or spiked with virginiamycin (VM) postfermentation were fed to cattle and effects on antimicrobial susceptibility, and prevalence of antimicrobial resistance genes in commensal bacteria was examined. Biological activity assays of DG (from each fermentation) indicated a concentration of 0, 0.7, and 8.9 mg/kg VM, respectively. Twenty-four crossbred beef steers were fed 1 of 4 diets (containing 8% of each of the different batches of DG) and a fourth using 8% of the control DG (0 mg/kg VM) + 0.025 g/kg V-Max50 (positive control) for 7 wk. Fecal samples were collected weekly throughout the experimental period and cultured for Escherichia coli and Enterococcus, and isolates were examined for antimicrobial susceptibility, antimicrobial resistance genes (vatE, ermB, and msrC in Enterococcus), and integrons (E. coli). No treatment differences (P > 0.05) were observed in antimicrobial susceptibility of the E. coli isolates. Enterococcus isolates were resistant to more antimicrobials; however, this was influenced by the species of Enterococcus and not treatment (P > 0.10). The prevalence of ermB was greater (P < 0.05) in the control isolates after 4 and 6 wk while at wk 7, prevalence was greater (P < 0.01) in the 0.7 and 8.9 mg/kg VM treatments. Taken together, the minor treatment differences observed for the presence of ermB coupled with the lack of effect on antimicrobial susceptibility patterns suggest that feeding DG containing VM residues should have minimal if any impact on prevalence of antimicrobial resistance.


Assuntos
Bovinos/microbiologia , Grão Comestível/química , Enterococcus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Fezes/microbiologia , Virginiamicina/farmacologia , Ração Animal/análise , Animais , Antibacterianos/farmacologia , Dieta/veterinária , Farmacorresistência Bacteriana , Masculino , Virginiamicina/química
5.
Int J Med Microbiol ; 304(1): 44-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24119565

RESUMO

Streptogramins are potent drugs against numerous highly resistant pathogens and therefore are used as antibiotics of last-resort human therapy. They consist of a mixture of two different types of chemical substances - the group A streptogramins, which are polyunsaturated macrolactones, and the group B streptogramins, representing cyclic hexadepsipeptides. Streptogramins are unique in their mode of action: each component alone exhibits a moderate bacteriostatic activity by binding to the bacterial 50S ribosomal subunit and thereby blocking translation, whereas the synergic combination of both substances is up to hundred fold more effective than the single compounds, resulting in a bactericidal activity. The streptogramin biosynthetic genes are organized as large antibiotic superclusters. These clusters harbour numerous regulatory genes, which encode different types of regulators that together form a complex hierarchical signalling system, which governs the regulation of streptogramin biosynthesis. Resistance is also regulated by this cascade. However, whereas resistance against streptogramins is quite well understood in diverse pathogenic organisms, only little is known about how the natural producer strains protect themselves against these toxic compounds. Here, we give an overview about the recent advances in streptogramin investigations with a main focus on the best-studied representatives, pristinamycin and virginiamycin. We concentrate on the biosynthesis of these compounds, their regulation and resistance determinants as well as their application in medicine and food industry.


Assuntos
Antibacterianos/farmacologia , Vias Biossintéticas/genética , Farmacorresistência Bacteriana , Viabilidade Microbiana/efeitos dos fármacos , Pristinamicina/farmacologia , Virginiamicina/farmacologia , Antibacterianos/biossíntese , Antibacterianos/química , Antibacterianos/uso terapêutico , Sinergismo Farmacológico , Indústria Alimentícia , Humanos , Pristinamicina/biossíntese , Pristinamicina/química , Pristinamicina/uso terapêutico , Virginiamicina/biossíntese , Virginiamicina/química , Virginiamicina/uso terapêutico
6.
Poult Sci ; 91(12): 3236-46, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23155036

RESUMO

A study was conducted to determine the effect of feeding high concentrations of corn distillers dried grains with solubles (DDGS) on egg production and the internal quality of eggs from laying hens. Four diets were formulated to contain 0, 17, 35, or 50% corn DDGS. A total of two hundred forty 54-wk-old Single-Comb White Leghorn laying hens were randomly allotted to 2 birds per cage with 3 consecutive cages representing an experimental unit (EU). Each EU was assigned to 1 of 4 dietary treatments according to a completely randomized design. Hens were fed for a 24-wk experimental period after transition feeding to gradually increase corn DDGS inclusion over a 4-wk period. Two sets of experimental diets were formulated, and each diet was fed for 12 wk. Egg production, feed consumption, egg component, yolk color, Haugh unit during storage times, and shell breaking strength were measured. Egg production, egg weight, egg mass, feed intake, and feed efficiency were adversely affected by the highest level of DDGS in the diet (50%) during the first 12-wk period. Once diets were reformulated to include an increased concentration of both lysine and methionine, differences among the dietary treatments were reduced, as the performance of the 50% DDGS diets was greatly improved. Over the last 6 wk of study, no differences in egg production, egg weight, and feed intake among DDGS treatments were found. The DDGS diets positively affected the internal quality of eggs during storage. Improved yolk color and Haugh unit were observed as the dietary DDGS levels increased, but the increase for Haugh unit was significant only when the DDGS level was 50%. Shell weight percentage was increased in the 50% DDGS diet, but no differences in yolk and albumen percentage were observed. It was concluded that up to 50% of DDGS could be included in the layer's diet without affecting egg weight, feed intake, egg mass, feed efficiency, and egg production as long as digestible amino acids were sufficient in DDGS-added diets.


Assuntos
Ração Animal/análise , Galinhas/fisiologia , Dieta/veterinária , Ovos/normas , Oviposição/efeitos dos fármacos , Zea mays/química , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antibacterianos/química , Relação Dose-Resposta a Droga , Feminino , Virginiamicina/química
8.
J AOAC Int ; 92(1): 329-39, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19382591

RESUMO

A liquid chromatographic-mass spectrometric (LC-MS) method was developed and validated for the determination and confirmation of virginiamycin (VMY) M1 residues in porcine liver, kidney, and muscle tissues at concentrations > or =2 ng/g. Porcine liver, kidney, or muscle tissue is homogenized with methanol-acetonitrile. After centrifugation, the supernatant is diluted with phosphate buffer and cleaned up on a C18 solid-phase extraction cartridge. VMY in the eluate is partitioned into chloroform and the aqueous upper layer is removed by aspiration. After evaporating the chloroform in the residual mixture to dryness, the dried extract is reconstituted in mobile phase and VMY is quantified by LC-MS. Any samples eliciting quantifiable levels of VMY M1 (i.e., at concentrations > or =2 ng/g) are subjected to confirmatory analysis by LC-MSIMS. VMY S1, a minor component of the VMY complex, is monitored but not quantified or confirmed.


Assuntos
Resíduos de Drogas/análise , Carne/análise , Virginiamicina/análise , Acetonitrilos , Animais , Cromatografia Líquida/métodos , Rim/química , Fígado/química , Espectrometria de Massas/métodos , Metanol , Modelos Moleculares , Músculo Esquelético/química , Suínos , Virginiamicina/química
9.
Org Lett ; 9(16): 3105-8, 2007 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-17608433

RESUMO

A de novo approach to the formal total synthesis of the macrolide natural product (-)-virginiamycin M2 has been achieved via a convergent approach. The absolute and relative stereochemistry of the nonpeptide portion of (-)-virginiamycin M2 was introduced by two Sharpless asymmetric dihydroxylation reactions.


Assuntos
Macrolídeos/síntese química , Virginiamicina/análogos & derivados , Virginiamicina/síntese química , Catálise , Macrolídeos/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Virginiamicina/química
10.
Biochim Biophys Acta ; 1774(5): 610-8, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17442646

RESUMO

The three-dimensional structure of acetylated virginiamycin M(1) (acetylated VM1) in chloroform and in a water/acetonitrile mixture (83:17 v/v) have been established through 2D high resolution NMR experiments and molecular dynamics modeling and the results compared with the conformation of the antibiotic VM1 in the same and other solvents. The results indicated that acetylation of the C-14 OH group of VM1 caused it to rotate about 90 degrees from the position it assumed in non-acetylated VM1. The conformation of both VM1 and acetylated VM1 appear to flatten in moving from a nonpolar to polar solvent. However, the acetylated form has a more hydrophobic nature. The acetylated VM1 in chloroform and in water/acetonitrile solution had a similar configuration to that of VM1 bound to 50S ribosomes and to the Vat(D) active sites as previously determined by X-ray crystallography. Docking studies of VM1 to the 50S ribosomal binding site and the Vat(D) gave conformations very similar to those derived from X-ray crystallographic studies. The docking studies with acetylated VM1 suggested the possibility of a hydrogen bond from the acetyl carbonyl group oxygen of acetylated VM1 to the 2' hydroxyl group of ribose of adenosine 2538 at the ribosomal VM1 binding site. No hydrogen bonds between acetylated VM1 and the Vat(D) active sites were found; the loss of this binding interaction partly accounts for the release of the product from the active site.


Assuntos
Solventes/química , Virginiamicina/química , Acetilação , Sítios de Ligação , Modelos Moleculares , Conformação Molecular
11.
Gene ; 393(1-2): 31-42, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17350183

RESUMO

Virginiamycin M (VM) of Streptomyces virginiae is a hybrid polyketide-peptide antibiotic with peptide antibiotic virginiamycin S (VS) as its synergistic counterpart. VM and VS belong to the Streptogramin family, which is characterized by strong synergistic antibacterial activity, and their water-soluble derivatives are a new therapeutic option for combating vancomycin-resistant Gram-positive bacteria. Here, the VM biosynthetic gene cluster was isolated from S. virginiae in the 62-kb region located in the vicinity of the regulatory island for virginiamycin production. Sequence analysis revealed that the region consists of 19 complete open reading frames (ORFs) and one C-terminally truncated ORF, encoding hybrid polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS), typical PKS, enzymes synthesizing precursors for VM, transporters for resistance, regulatory proteins, and auxiliary enzymes. The involvement of the cloned gene cluster in VM biosynthesis was confirmed by gene disruption of virA encoding a hybrid PKS-NRPS megasynthetase, which resulted in complete loss of VM production without any effect on VS production. To assemble the VM core structure, VirA, VirF, VirG, and VirH consisting, as a whole, of 24 domains in 8 PKS modules and 7 domains in 2 NRPS modules were predicted to act as an acyltransferase (AT)-less hybrid PKS-NRPS, whereas VirB, VirC, VirD, and VirE are likely to be essential for the incorporation of the methyl group into the VM framework by a HMG-CoA synthase-based reaction. Among several uncommon features of gene organization in the VM gene cluster, the lack of AT domain in every PKS module and the presence of a discrete AT encoded by virI are notable. AT-overexpression by an additional copy of virI driven by ermEp() resulted in 1.5-fold increase of VM production, suggesting that the amount of VirI is partly limiting VM biosynthesis.


Assuntos
Antibacterianos/biossíntese , Genes Bacterianos , Família Multigênica/genética , Estreptograminas/biossíntese , Streptomyces/genética , Streptomyces/metabolismo , Virginiamicina/biossíntese , Aciltransferases/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Pareamento de Bases/genética , Sequência de Bases , DNA Bacteriano/genética , Farmacorresistência Bacteriana/genética , Regulação Bacteriana da Expressão Gênica , Modelos Genéticos , Dados de Sequência Molecular , Mutagênese Insercional , Peptídeo Sintases/metabolismo , Filogenia , Policetídeo Sintases/química , Policetídeo Sintases/metabolismo , Estrutura Terciária de Proteína , Recombinação Genética/genética , Análise de Sequência de Proteína , Estreptograminas/química , Transcrição Genética , Virginiamicina/química
12.
Cell ; 121(2): 257-70, 2005 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-15851032

RESUMO

Crystal structures of H. marismortui large ribosomal subunits containing the mutation G2099A (A2058 in E. coli) with erythromycin, azithromycin, clindamycin, virginiamycin S, and telithromycin bound explain why eubacterial ribosomes containing the mutation A2058G are resistant to them. Azithromycin binds almost identically to both G2099A and wild-type subunits, but the erythromycin affinity increases by more than 10(4)-fold, implying that desolvation of the N2 of G2099 accounts for the low wild-type affinity for macrolides. All macrolides bind similarly to the H. marismortui subunit, but their binding differs significantly from what has been reported in the D. radioidurans subunit. The synergy in the binding of streptogramins A and B appears to result from a reorientation of the base of A2103 (A2062, E. coli) that stacks between them. The structure of large subunit containing a three residue deletion mutant of L22 shows a change in the L22 structure and exit tunnel shape that illuminates its macrolide resistance phenotype.


Assuntos
Antibacterianos/química , Farmacorresistência Bacteriana/fisiologia , Eritromicina/química , Haloarcula marismortui/química , Ribossomos/química , Antibacterianos/metabolismo , Azitromicina/química , Azitromicina/metabolismo , Sítios de Ligação , Clindamicina/química , Clindamicina/metabolismo , Cristalografia , Eritromicina/metabolismo , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Haloarcula marismortui/genética , Haloarcula marismortui/metabolismo , Cetolídeos/química , Cetolídeos/metabolismo , Mutação , Ligação Proteica , RNA Ribossômico 23S/química , RNA Ribossômico 23S/genética , RNA Ribossômico 23S/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Virginiamicina/química , Virginiamicina/metabolismo
13.
Chemotherapy ; 50(5): 260-4, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15528893

RESUMO

BACKGROUND: Quinupristin-dalfopristin (Q-D) is a mixture of quinupristin and dalfopristin, which are semisynthetic antibiotics of streptogramin groups B and A, respectively. METHODS: We compared the effect of Q-D to that of vancomycin (VCM) in murine models of hematogenous pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and VCM-insensitive S. aureus (VISA). RESULTS: Treatment with Q-D resulted in a significant decrease in the number of viable bacteria in the lungs of mice in an MRSA infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 2.99 +/- 0.44, 6.38 +/- 0.32, 5.75 +/- 0.43 and 8.40 +/- 0.14 log10 CFU/lung, respectively]. Compared with VCM, high-dose Q-D significantly reduced the number of bacteria detected in the VISA hematogenous infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 5.17 +/- 0.52, 7.03 +/- 0.11, 7.10 +/- 0.49 and 7.18 +/- 0.36 log10 CFU/lung, respectively]. Histopathological examination confirmed the effect of Q-D. CONCLUSION: Our results suggest that Q-D is potent and effective in the treatment of MRSA and VISA hematogenous pulmonary infections.


Assuntos
Bacteriemia/complicações , Modelos Animais de Doenças , Resistência a Meticilina/efeitos dos fármacos , Pneumonia Estafilocócica/complicações , Pneumonia Estafilocócica/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Resistência a Vancomicina/efeitos dos fármacos , Virginiamicina/uso terapêutico , Animais , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência Microbiana a Medicamentos , Japão , Pulmão/microbiologia , Pulmão/fisiopatologia , Pulmão/ultraestrutura , Masculino , Resistência a Meticilina/genética , Camundongos , Camundongos Endogâmicos , Organismos Livres de Patógenos Específicos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Resistência a Vancomicina/genética , Virginiamicina/química , Virginiamicina/farmacologia
14.
J Mol Biol ; 330(5): 1061-75, 2003 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12860128

RESUMO

Structures of anisomycin, chloramphenicol, sparsomycin, blasticidin S, and virginiamycin M bound to the large ribosomal subunit of Haloarcula marismortui have been determined at 3.0A resolution. Most of these antibiotics bind to sites that overlap those of either peptidyl-tRNA or aminoacyl-tRNA, consistent with their functioning as competitive inhibitors of peptide bond formation. Two hydrophobic crevices, one at the peptidyl transferase center and the other at the entrance to the peptide exit tunnel play roles in binding these antibiotics. Midway between these crevices, nucleotide A2103 of H.marismortui (2062 Escherichia coli) varies in its conformation and thereby contacts antibiotics bound at either crevice. The aromatic ring of anisomycin binds to the active-site hydrophobic crevice, as does the aromatic ring of puromycin, while the aromatic ring of chloramphenicol binds to the exit tunnel hydrophobic crevice. Sparsomycin contacts primarily a P-site bound substrate, but also extends into the active-site hydrophobic crevice. Virginiamycin M occupies portions of both the A and P-site, and induces a conformational change in the ribosome. Blasticidin S base-pairs with the P-loop and thereby mimics C74 and C75 of a P-site bound tRNA.


Assuntos
Antibacterianos/química , Ribossomos/química , Anisomicina/química , Sítios de Ligação , Ligação Competitiva , Cloranfenicol/química , Cristalografia por Raios X , Elétrons , Haloarcula/metabolismo , Íons , Modelos Moleculares , Nucleosídeos/química , Peptídeos/química , Conformação Proteica , RNA de Transferência/metabolismo , Esparsomicina/química , Virginiamicina/química
16.
J Bacteriol ; 184(18): 5151-7, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12193632

RESUMO

From Streptomyces virginiae, in which production of streptogramin antibiotic virginiamycin M(1) and S is tightly regulated by a low-molecular-weight Streptomyces hormone called virginiae butanolide (VB), which is a member of the gamma-butyrolactone autoregulators, the hormone biosynthetic gene (barS1) was cloned and characterized by heterologous expression in Escherichia coli and by gene disruption in S. virginiae. The barS1 gene (a 774-bp open reading frame encoding a 257-amino-acid protein [M(r), 27,095]) is situated in the 10-kb regulator island surrounding the VB-specific receptor gene, barA. The deduced BarS1 protein is weakly homologous to beta-ketoacyl-acyl carrier protein/coenzyme A reductase and belongs to the superfamily of short-chain alcohol dehydrogenase. The function of the BarS1 protein in VB biosynthesis was confirmed by BarS1-dependent in vitro conversion of 6-dehydro-VB-A to VB-A, the last catalytic step in VB biosynthesis. Of the four possible enantiomeric products from racemic 6-dehydro-VB-A as a substrate, only the natural enantiomer of (2R,3R,6S)-VB-A was produced by the purified recombinant BarS1 (rBarS1), indicating that rBarS1 is the stereospecific reductase recognizing (3R)-isomer as a substrate and reducing it stereospecifically to the (6S) product. In the DeltabarS1 mutant created by homologous recombination, the production of VB as well as the production of virginiamycin was lost. The production of virginiamycin by the DeltabarS1 mutant was fully recovered by the external addition of VB to the culture, which indicates that the barS1 gene is essential in the biosynthesis of the autoregulator VBs in S. virginiae and that the failure of virginiamycin production was a result of the loss of VB production.


Assuntos
4-Butirolactona/biossíntese , Oxirredutases do Álcool/genética , Antibacterianos/biossíntese , Proteínas de Bactérias/genética , Genes Reguladores , Streptomyces/genética , Virginiamicina/biossíntese , Oxirredutases do Álcool/química , Oxirredutases do Álcool/metabolismo , Sequência de Aminoácidos , Antibacterianos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Dados de Sequência Molecular , Fases de Leitura Aberta/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Recombinação Genética , Streptomyces/crescimento & desenvolvimento , Streptomyces/metabolismo , Virginiamicina/química
17.
Ann Fr Anesth Reanim ; 21(5): 424-30, 2002 May.
Artigo em Francês | MEDLINE | ID: mdl-12078438

RESUMO

Research efforts to discover new compounds active against staphylococci are more than ever justified today. The incidence of methicillin-resistant staphylococci remains very high in hospitals, and the solution provided by glycopeptides is far from being satisfactory. These compounds exhibit mediocre pharmacokinetic and pharmacodynamic properties. Their ease and safety of use are poor. Finally, strains with diminished sensitivity to these antibiotics are beginning to appear. This article examines the opportunities offered by two new anti-staphylococcal agents: quinupristine-dalfopristine (Synercid) and linezolide (not marketed in France).


Assuntos
Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Acetamidas/uso terapêutico , Antibacterianos/química , Antibacterianos/farmacocinética , Quimioterapia Combinada/química , Quimioterapia Combinada/farmacocinética , Quimioterapia Combinada/uso terapêutico , Humanos , Linezolida , Oxazolidinonas/uso terapêutico , Infecções Estafilocócicas/microbiologia , Virginiamicina/análogos & derivados , Virginiamicina/química , Virginiamicina/farmacocinética , Virginiamicina/uso terapêutico
18.
Prikl Biokhim Mikrobiol ; 37(3): 301-8, 2001.
Artigo em Russo | MEDLINE | ID: mdl-11443899

RESUMO

A method for chromatographic separation and quantitative determination of individual components of the antibiotic virginiamycin, produced by microbiological synthesis (Streptomyces virginiae strain 147), is described. The components, M1-2 and S1-5, were isolated from fermentation broth and identified by HPTLC and HPLC (the results obtained using the two methods correlate well with each other). Conditions of culturing of the producer and compositions of nutritive media were optimized. Using UV irradiation as a mutagenic factor, the producer was selected for increased level of synthesis of the antibiotic; this was achieved by inducing mutations that impart resistance to virginiamycin and meta-fluorophenylalanine, an analog of phenylalanine.


Assuntos
Antibacterianos/química , Streptomyces/química , Virginiamicina/química , Antibacterianos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Mutação , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Streptomyces/isolamento & purificação , Virginiamicina/isolamento & purificação
19.
EMBO Rep ; 2(4): 318-23, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11306553

RESUMO

Ribosomal antibiotics must discriminate between bacterial and eukaryotic ribosomes to various extents. Despite major differences in bacterial and eukaryotic ribosome structure, a single nucleotide or amino acid determines the selectivity of drugs affecting protein synthesis. Analysis of resistance mutations in bacteria allows the prediction of whether cytoplasmic or mitochondrial ribosomes in eukaryotic cells will be sensitive to the drug. This has important implications for drug specificity and toxicity. Together with recent data on the structure of ribosomal subunits these data provide the basis for development of new ribosomal antibiotics by rationale drug design.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ribossomos/metabolismo , Alelos , Citoplasma/metabolismo , Bases de Dados Factuais , Desenho de Fármacos , Lincomicina/química , Macrolídeos , Mitocôndrias/metabolismo , Mutação , Mycobacterium smegmatis/metabolismo , Plasmídeos/metabolismo , RNA Ribossômico 16S/química , RNA Ribossômico 16S/metabolismo , Relação Estrutura-Atividade , Fatores de Tempo , Virginiamicina/química
20.
Acta Crystallogr A ; 56(Pt 6): 525-8, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11058837

RESUMO

Simulated annealing is used to solve the X-ray phase problem formulated as a minimization problem. The cost function consists of two parts, one represents the discrepancy between measured and calculated intensities while the other monitors the probability distribution of the triplets. From a random real-space structure at the start, the atoms are moved one by one to gradually reduce the cost function until the best structure emerges. Trial calculations for structures including hexadecaisoleucinomycin (HEXIL) are presented. Comparison of this method with other related methods is made.


Assuntos
Cristalografia por Raios X , Valinomicina/análogos & derivados , Virginiamicina/química , Cristalografia por Raios X/métodos , Ionóforos/química , Modelos Moleculares , Conformação Molecular , Valinomicina/química
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