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PubMed1997

The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation.

Deletion of most of the coding region of the ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) resulted in loss of ppGpp synthesis, both upon entry into stationary phase under conditions of nitrogen limitation and following amino acid starvation during exponential growth, but had no effect on growth rate. The relA mutant, which showed continued rRNA synthesis upon amino acid depletion (the relaxed response), failed to produce the antibiotics undecylprodigiosin (Red) and actinorhodin (Act) under conditions of nitrogen limitation. The latter appears to reflect diminished transcription of pathway-specific regulatory genes for Red and Act production, redD and actII-ORF4, respectively. In addition to the changes in secondary metabolism, the relA mutant showed a marked delay in the onset and extent of morphological differentiation, resulting in a conspicuously altered colony morphology.

Anthraquinones↗
PubMed1997

bldA dependence of undecylprodigiosin production in Streptomyces coelicolor A3(2) involves a pathway-specific regulatory cascade.

The production of the red-pigmented tripyrrole antibiotic undecylprodigiosin (Red) by Streptomyces coelicolor A3(2) depends on two pathway-specific regulatory genes, redD and redZ. RedD is homologous to several other proteins that regulate antibiotic production in streptomycetes; RedZ is a member of the response regulator family. redZ transcripts were detected during exponential growth and increased in amount during transition and stationary phases; transcription of redD was confined to the two latter stages of growth. Whereas mutation of redD had no effect on redZ transcription, transcription of redD was highly dependent on redZ, suggesting that RedZ is a transcriptional activator of redD. bldA, which encodes the only tRNA of S. coelicolor that can efficiently translate the rare leucine codon UUA, is required for Red production at higher phosphate concentrations. While the redD transcript contains no UUA codons, the redZ mRNA contains one. Transcription of redZ appeared to be unaffected in a bldA mutant; in contrast, redD transcription was undetectable, consistent with the translational dependence of redZ on bldA and the transcriptional dependence of redD on redZ. Red production in a bldA mutant was restored by multiple copies of redZ, presumably reflecting a low level of mistranslation of the redZ UUA codon, while multiple copies of redD had no effect, presumably a consequence of the severe dependence of redD transcription on RedZ. Transcription of redZ appears to be negatively autoregulated.

Anti-Bacterial Agents↗
PubMed2001

Role of acid metabolism in Streptomyces coelicolor morphological differentiation and antibiotic biosynthesis.

Studies of citrate synthase (CitA) were carried out to investigate its role in morphological development and biosynthesis of antibiotics in Streptomyces coelicolor. Purification of CitA, the major vegetative enzyme activity, allowed characterization of its kinetic properties. The apparent K(m) values of CitA for acetyl coenzyme A (acetyl-CoA) (32 microM) and oxaloacetate (17 microM) were similar to those of citrate synthases from other gram-positive bacteria and eukaryotes. CitA was not strongly inhibited by various allosteric feedback inhibitors (NAD(+), NADH, ATP, ADP, isocitrate, or alpha-ketoglutarate). The corresponding gene (citA) was cloned and sequenced, allowing construction of a citA mutant (BZ2). BZ2 was a glutamate auxotroph, indicating that citA encoded the major citrate synthase allowing flow of acetyl-CoA into the tricarboxylic acid (TCA) cycle. Interruption of aerobic TCA cycle-based metabolism resulted in acidification of the medium and defects in morphological differentiation and antibiotic biosynthesis. These developmental defects of the citA mutant were in part due to a glucose-dependent medium acidification that was also exhibited by some other bald mutants. Unlike other acidogenic bald strains, citA and bldJ mutants were able to produce aerial mycelia and pigments when the medium was buffered sufficiently to maintain neutrality. Extracellular complementation studies suggested that citA defines a new stage of the Streptomyces developmental cascade.

Anthraquinones↗
PubMed2002

Activation of antibiotic biosynthesis by specified mutations in the rpoB gene (encoding the RNA polymerase beta subunit) of Streptomyces lividans.

We found that the biosynthesis of actinorhodin (Act), undecylprodigiosin (Red), and calcium-dependent antibiotic (CDA) are dramatically activated by introducing certain mutations into the rpoB gene that confer resistance to rifampin to Streptomyces lividans 66, which produces less or no antibiotics under normal growth conditions. Activation of Act and/or Red biosynthesis by inducing mutations in the rpoB gene was shown to be dependent on the mutation's position and the amino acid species substituted in the beta-subunit of the RNA polymerase. Mutation analysis identified 15 different kinds of point mutations, which are located in region I, II, or III of the rpoB gene and, in addition, two novel mutations (deletion of nucleotides 1287 to 1289 and a double substitution at nucleotides 1309 and 1310) were also found. Western blot analyses and S1 mapping analyses demonstrated that the expression of actII-ORF4 and redD, which are pathway-specific regulatory genes for Act and Red, respectively, was activated in the mutants able to produce Act and Red. The ActIV-ORF1 protein (an enzyme for Act biosynthesis) and the RedD protein were produced just after the upregulation of ActII-ORF4 and RedZ, respectively. These results indicate that the mutation in the rpoB gene of S. lividans, resulting in the activation of Act and/or Red biosynthesis, functions at the transcription level by activating directly or indirectly the key regulatory genes, actII-ORF4 and redD. We propose that the mutated RNA polymerase may function by mimicking the ppGpp-bound form in activating the onset of secondary metabolism in STREPTOMYCES:

Amino Acid Sequence↗
PubMed2005

The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family.

The bldC locus, required for formation of aerial hyphae in Streptomyces coelicolor, was localized by map-based cloning to the overlap between cosmids D17 and D25 of a minimal ordered library. Subcloning and sequencing showed that bldC encodes a member of a previously unrecognized family of small (58- to 78-residue) DNA-binding proteins, related to the DNA-binding domains of the MerR family of transcriptional activators. BldC family members are found in a wide range of gram-positive and gram-negative bacteria. Constructed DeltabldC mutants were defective in differentiation and antibiotic production. They failed to form an aerial mycelium on minimal medium and showed severe delays in aerial mycelium formation on rich medium. In addition, they failed to produce the polyketide antibiotic actinorhodin, and bldC was shown to be required for normal and sustained transcription of the pathway-specific activator gene actII-orf4. Although DeltabldC mutants produced the tripyrrole antibiotic undecylprodigiosin, transcripts of the pathway-specific activator gene (redD) were reduced to almost undetectable levels after 48 h in the bldC mutant, in contrast to the bldC+ parent strain in which redD transcription continued during aerial mycelium formation and sporulation. This suggests that bldC may be required for maintenance of redD transcription during differentiation. bldC is expressed from a single promoter. S1 nuclease protection assays and immunoblotting showed that bldC is constitutively expressed and that transcription of bldC does not depend on any of the other known bld genes. The bldC18 mutation that originally defined the locus causes a Y49C substitution that results in instability of the protein.

Amino Acid Substitution↗
PubMed2002

Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin.

Janus kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2-induced cell proliferation, also blocks IL-2-mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression.

Administration, Oral↗
PubMed2004

Janus kinase 3: a novel target for selective transplant immunosupression.

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.

Amino Acid Sequence↗
PubMed1996

Effect of metacycloprodigiosin, an inhibitor of killer T cells on murine skin and heart transplants.

Metacycloprodigiosin is an antibiotic that has been shown to suppress T-cell proliferation induced by concanavalin A in vitro. We examined the effect of metacycloprodigiosin on murine allogenic skin and heart transplantation models, and compared graft rejection with donor-specific cytotoxic T-cells and antibody activity. The antibiotic slightly prolonged the survival of C57Bl/6 heart and skin grafts in BALB/c mice, although the effect was less that that of cyclosporin A. The effect was more evident in Bm1 (H-2D mutant) skin grafts on C57B1/6 hosts or in a minor histocompatibility antigen-mismatched model. In contrast, metacycloprodigiosin suppressed anti-graft cytotoxic T-cell activity of BALB/c spleen grafted with C57B1/6 skin as comparable to cyclosporin A, but had only partial effect on antibody production. Thus, metacycloprodigiosin is more effective in reducing splenic cytotoxic T-cell activity than in prolonging murine skin or cardiac allografts.

Animals↗
PubMed1975

[Effectiveness of prodigiozan in the therapy of chronic nonspecific diseases of the lungs].

The efficiency of the Soviet prodigiozan in therapy of chronic non-specific diseases of the lungs (18 cases with bronchial asthma and 26 cases with chronic pneumonia of the 1st and 2nd stages) in the phase of exacerbation was studied. The results of the treatment were estimated by the clinico-roentgenological pictures. The effect of prodigiozan on breathing and the functional state of the adrenal gland was studied in particular. Satisfactory results were obtained in the patients suffering from chronic pneumonia of the 1st and 2nd stages without clinical signs of the bronchial tree affection and in the patients with infection-allergic forms of bronchial asthma. Modest results were observed in the patients suffering from chronic pneumonia of the 1st and 2nd stages with the bronchial tree affection, especially when exacerbated by the asthma syndrome. In some patients the results of the treatment with prodigiozan were not stable. Prodigiozan improved the bronchial permeability, stimulated the sympatho-adrenal system and had no effect on the adrenal cortex.

11-Hydroxycorticosteroids↗
PubMed2000

Rapid extracellular acidification induced by glucose metabolism in non-proliferating cells of Serratia marcescens.

The addition of glucose or other sugars to resting cells of Serratia maurcescens induced rapid acidification of the extracellular medium. This acidification was due to the catabolism of sugars. The rate of acidification depended on the carbon source and its concentration. HPLC analysis of the supernatants demonstrated that the progressive fall in pH resulted from the rapid production of lactic, acetic, pyruvic and citric acids. Other microorganisms were tested for their ability to produce this rapid acidification of the medium. This study may provide a rapid and simple method for metabolism studies.

Acetic Acid↗
PubMed2000

Application of redD, the transcriptional activator gene of the undecylprodigiosin biosynthetic pathway, as a reporter for transcriptional activity in Streptomyces coelicolor A3(2) and Streptomyces lividans.

redD encodes the transcriptional activator of the biosynthetic pathway for undecylprodigiosin, a red-pigmented, mycelium-bound antibiotic made by Streptomyces coelicolor A3(2) and Streptomyces lividans. A promoterless version of redD preceded by the efficiently used tuf1 ribosome binding site was inserted into two different plasmid vectors, providing a convenient reporter of transcriptional activity in both species. One plasmid, plJ2587, replicates autonomously in both Escherichia coli and streptomycetes, while the other, plJ2585, replicates in E. coli and can be transferred to streptomycetes by conjugation or transformation, whereupon it integrates stably at the chromosomal attachment site for the temperate phage phiC31. The utility of the plasmids in detecting not only transcriptional activity, but also its regulation, was confirmed using the rrnAp, ermEp*, and glnRp promoters. The ability to screen visually and spectrophotometrically for red pigmentation should make the vectors particularly attractive for analysing the regulation of gene expression, and for the isolation of mutants, in both S. coelicolor and S. lividans.

Amino Acid Sequence↗
PubMed1975

[Effect of carbenicillin and its combination with prodigiozan and lysozyme on the course of an experimental inflammatory process of Proteus etiology].

Biological properties of 142 Proteus strains isolated from patients were studied. Sensitivity of Proteus to II antibiotics was tested. The isolates were resistant to most of the antibiotics. The highest number of the isolates was sensitive to ampicillin (77.1 minus or plus 7.16) and especially to carbenicillin (82.6 plus or minus 6.16). This provided the use of carbenicillin for the treatment of experimental septicemia in albino mice and wound processes in rabbits with Proteus complications. The high therapeutic effect of the antibiotic was shown in experiments with 210 albino mice and 44 rabbits. The therapeutic effect of carbenicillin increased when it was used in combination with prodigiozan and especially in combination with prodigiozan and lysozyme.

Animals↗