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1.
J Ind Microbiol Biotechnol ; 35(10): 1131-8, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18651189

RESUMO

A40926 is a glycopeptide antibiotic complex consisting of several structurally related factors. It is produced by fermentation of Nonomuraea sp. ATCC 39727 and the complex components differ in the structure of the fatty acid moiety linked to the aminoglucuronic acid unit. In previous work, we observed that the production of single factors in glycopeptide antibiotic complexes could be selectively enhanced by the addition of suitable precursors to the culture medium. In this contribution, we examine the effects of branched amino acid addition to fermentation of Nonomuraea sp. in a chemically defined minimal medium. The changes in the composition of cell fatty acids correlate to the fatty acid distribution within the A40926 complex in diverse cultivation conditions. Nonomuraea sp. prefers isobutyric, butyric and propionic acids as initiators of fatty acid biosynthesis. The relative amount of the produced fatty acids is significantly influenced by the availability of intermediates or final products from the amino acid catabolic pathways. Antibiotic complex composition closely reflects the cell fatty acid pattern, in agreement with the assumption that the antibiotic fatty acid moieties are synthesized by shortening the chain of cell fatty acids.


Assuntos
Actinomycetales/metabolismo , Aminoácidos/metabolismo , Antibacterianos/metabolismo , Ácidos Graxos/metabolismo , Microbiologia Industrial , Teicoplanina/análogos & derivados , Actinomycetales/química , Meios de Cultura/química , Meios de Cultura/metabolismo , Ácidos Graxos/química , Fermentação , Teicoplanina/química , Teicoplanina/metabolismo
2.
Biochemistry ; 46(20): 5884-95, 2007 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-17469849

RESUMO

Important classes of antibiotics acting on bacterial cell wall biosynthesis, such as beta-lactams and glycopeptides, are used extensively in therapy and are now faced with a challenge because of the progressive spread of resistant pathogens. A discovery program was devised to target novel peptidoglycan biosynthesis inhibitors capable of overcoming these resistance mechanisms. The microbial products were first screened according to their differential activity against Staphylococcus aureus and its L-form. Then, activities insensitive to the addition of a beta-lactamase cocktail or d-alanyl-d-alanine affinity resin were selected. Thirty-five lantibiotics were identified from a library of broth extracts produced by 40,000 uncommon actinomycetes. Five of them showed structural characteristics that did not match with any known microbial metabolite. In this study, we report on the production, structure determination, and biological activity of one of these novel lantibiotics, namely, planosporicin, which is produced by the uncommon actinomycete Planomonospora sp. Planosporicin is a 2194 Da polypeptide originating from 24 proteinogenic amino acids. It contains lanthionine and methyllanthionine amino acids generating five intramolecular thioether bridges. Planosporicin selectively blocks peptidoglycan biosynthesis and causes accumulation of UDP-linked peptidoglycan precursors in growing bacterial cells. On the basis of its mode of action and globular structure, planosporicin can be assigned to the mersacidin (20 amino acids, 1825 Da) and the actagardine (19 amino acids, 1890 Da) subgroup of type B lantibiotics. Considering its spectrum of activity against Gram-positive pathogens of medical importance, including multi-resistant clinical isolates, and its efficacy in vivo, planosporicin represents a potentially new antibiotic to treat emerging pathogens.


Assuntos
Actinomycetales/metabolismo , Bacteriocinas/química , Parede Celular/metabolismo , Actinomycetales/química , Sequência de Aminoácidos , Animais , Antibacterianos/biossíntese , Antibacterianos/química , Antibacterianos/classificação , Antibacterianos/farmacologia , Bacteriocinas/biossíntese , Bacteriocinas/classificação , Bacteriocinas/farmacologia , Parede Celular/química , Feminino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
3.
Biochemistry ; 45(11): 3692-702, 2006 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-16533052

RESUMO

In the course of a microbial product screening aimed at the discovery of novel antibiotics acting on bacterial protein synthesis, a complex of three structurally related tetrapeptides, namely, GE81112 factors A, B, and B1, was isolated from a Streptomyces sp. The screening was based on a cell-free assay of bacterial protein synthesis driven by a model mRNA containing natural initiation signals. In this study we report the production, isolation, and structure determination of these novel, potent and selective inhibitors of cell-free bacterial protein synthesis, which stably bind the 30S ribosomal subunit and inhibit the formation of fMet-puromycin. They did not inhibit translation by yeast ribosomes in vitro. Spectroscopic analyses revealed that they are tetrapeptides constituted by uncommon amino acids. While GE81112 factors A, B, and B1 were effective in inhibiting bacterial protein synthesis in vitro, they were less active against Gram-positive and Gram-negative bacterial cells. Cells grown in minimal medium were more susceptible to the compounds than those grown in rich medium, and this is most likely due to competition or regulation by medium components during peptide uptake. The novelty of the chemical structure and of the specific mode of action on the initiation phase of bacterial protein synthesis makes GE81112 a unique scaffold for designing new drugs.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Peptídeos/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Streptomyces/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Escherichia coli/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Iniciação Traducional da Cadeia Peptídica/efeitos dos fármacos , Peptídeos/química , Peptídeos/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Fatores de Tempo
4.
FEMS Microbiol Lett ; 256(2): 229-35, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16499611

RESUMO

The actinomycete Nonomuraea sp. ATCC39727 produces the glycopeptide A40926. In the corresponding dbv cluster, ORF28 encodes a putative hydroxylase. A gene replacement mutant of ORF28 in Nonomuraea produces a small amount of an A40926-related metabolite, 16 amu smaller than the parent compound, which was identified as the desoxyderivative of A40926 lacking the beta-hydroxyl group on the tyrosine moiety. This result demonstrates that ORF28 is actually involved in the formation of the beta-hydroxytyrosine residue present in A40926. The formation of an altered glycopeptide and the inability to rescue A40926 production upon feeding free beta-hydroxytyrosine are consistent with the possibility that, in contrast to balhimycin formation, hydroxylation occurs after tyrosine activation by the nonribosomal peptide synthetase.


Assuntos
Actinomycetales/enzimologia , Oxigenases de Função Mista/genética , Teicoplanina/análogos & derivados , Actinomycetales/genética , Actinomycetales/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/fisiologia , Di-Hidroxifenilalanina/biossíntese , Deleção de Genes , Hidroxilação , Oxigenases de Função Mista/fisiologia , Estrutura Molecular , Mutagênese Insercional , Teicoplanina/química , Teicoplanina/metabolismo , Tirosina/metabolismo
5.
J Antibiot (Tokyo) ; 57(1): 37-44, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15032484

RESUMO

In actinomycetes the catabolism products of branched chain amino acids provide biosynthetic precursors for the formation of several lipid-containing antibiotics. We have determined in Nonomuraea sp. ATCC 39727 the effect of valine on production of glycopeptide antibiotic A40926, which is a complex of factors structurally differing in fatty acid moieties. Addition of valine to minimal medium increased A40926 production and modified complex composition towards a mono-component. Similar results were also obtained in a rich production medium.


Assuntos
Actinobacteria/metabolismo , Antibacterianos/biossíntese , Glicopeptídeos , Valina/metabolismo , Antibacterianos/química , Cromatografia Líquida de Alta Pressão , Ácidos Graxos/metabolismo , Fermentação , Estrutura Molecular , Teicoplanina/análogos & derivados
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