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Kozo Ochi - One of the best experts on this subject based on the ideXlab platform.
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Metabolic perturbation to enhance polyketide and nonribosomal peptide Antibiotic Production using triclosan and ribosome-targeting drugs
Applied Microbiology and Biotechnology, 2017Co-Authors: Yukinori Tanaka, Masumi Izawa, Yoshikazu Hiraga, Yuya Misaki, Tomoko Watanabe, Kozo OchiAbstract:Although transcriptional activation of pathwayspecific positive regulatory genes and/or biosynthetic genes is primarily important for enhancing secondary metabolite Production, reinforcement of substrate supply, as represented by primary metabolites, is also effective. For example, partial inhibition of fatty acid synthesis with ARC2 (an analog of triclosan) was found to enhance polyketide Antibiotic Production. Here, we demonstrate that this approach is effective even for industrial high-producing strains, for example enhancing salinomycin Production by 40%, reaching 30.4 g/l of salinomycin in an industrial Streptomyces albus strain. We also hypothesized that a similar approach would be applicable to another important Antibiotic group, nonribosomal peptide (NRP) Antibiotics. We therefore attempted to partially inhibit protein synthesis by using ribosome-targeting drugs at subinhibitory concentrations (1/50∼1/2 of MICs), which may result in the preferential recruitment of intracellular amino acids to the biosynthesis of NRP Antibiotics rather than to protein synthesis. Among the ribosome-targeting drugs examined, chloramphenicol at subinhibitory concentrations was most effective at enhancing the Production by Streptomyces of NRP Antibiotics such as actinomycin, calcium-dependent Antibiotic (CDA), and piperidamycin, often resulting in an almost 2-fold increase in Antibiotic Production. Chloramphenicol activated biosynthetic genes at the transcriptional level and increased amino acid pool sizes 1.5- to 6-fold, enhancing the Production of actinomycin and CDA. This “metabolic perturbation” approach using subinhibitory concentrations of ribosome-targeting drugs is a rational method of enhancing NRP Antibiotic Production, being especially effective in transcriptionally activated (e.g., rpoB mutant) strains. Because this approach does not require prior genetic information, it may be widely applicable for enhancing bacterial Production of NRP Antibiotics and bioactive peptides.
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Improved Antibiotic Production and silent gene activation in Streptomyces diastatochromogenes by ribosome engineering.
The Journal of antibiotics, 2015Co-Authors: Xuping Shentu, Liu Nannan, Yukinori Tanaka, Kozo OchiAbstract:Improved Antibiotic Production and silent gene activation in Streptomyces diastatochromogenes by ribosome engineering
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The G243D mutation (afsB mutation) in the principal sigma factor σHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2)
Microbiology, 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor σ HrdB. Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB+ parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.
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The G243D mutation (afsB mutation) in the principal sigma factor sigmaHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2).
Microbiology (Reading England), 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor sigma(HrdB). Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB(+) parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.
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dramatic activation of Antibiotic Production in streptomyces coelicolor by cumulative drug resistance mutations
Applied and Environmental Microbiology, 2008Co-Authors: Guojun Wang, Takeshi Hosaka, Kozo OchiAbstract:We recently described a new method to activate Antibiotic Production in bacteria by introducing a mutation conferring resistance to a drug such as streptomycin, rifampin, paromomycin, or gentamicin. This method, however, enhanced Antibiotic Production by only up to an order of magnitude. Working with Streptomyces coelicolor A3(2), we established a method for the dramatic activation of Antibiotic Production by the sequential introduction of multiple drug resistance mutations. Septuple and octuple mutants, C7 and C8, thus obtained by screening for resistance to seven or eight drugs, produced huge amounts (1.63 g/liter) of the polyketide Antibiotic actinorhodin, 180-fold higher than the level produced by the wild type. This dramatic overProduction was due to the acquisition of mutant ribosomes, with aberrant protein and ppGpp synthesis activity, as demonstrated by in vitro protein synthesis assays and by the abolition of Antibiotic overProduction with relA disruption. This new approach, called "ribosome engineering," requires less time, cost, and labor than other methods and may be widely utilized for bacterial strain improvement.
Mervyn J. Bibb - One of the best experts on this subject based on the ideXlab platform.
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Manipulating and understanding Antibiotic Production in Streptomyces coelicolor A3(2) with decoy oligonucleotides
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Michael Mcarthur, Mervyn J. BibbAbstract:We have adapted and extended the decoy oligonucleotide technique for use in prokaryotes. To identify cis-acting regulatory elements within a promoter, we developed a DNase I/T7 exonuclease footprinting technique and applied it to actII-orf4 from Streptomyces coelicolor A3(2), which encodes the pathway-specific activator for Production of the Antibiotic actinorhodin. Our in vivo mapping data allowed us to create decoy oligonucleotides incorporating the identified regulatory elements and to test whether their introduction into S. coelicolor affected Antibiotic Production. We mapped the promoter region when in a transcriptionally inactive state before the onset of actinorhodin Production with the aim of designing decoy oligonucleotides capable of interfering with potential repressor binding and so stimulate actinorhodin Production. Mapping identified five candidates for decoy oligonucleotides, and these were tested in a plate-based assay to rapidly validate their activity. A transfection protocol was developed for liquid cultures that enabled efficient uptake of decoys, and quantitative real-time PCR demonstrated decoy persistence for >70 h. Measurement of the effects on growth, expression of actII-orf4, and Antibiotic Production demonstrated that one of the decoys, in concordance with the plate assay, was more efficacious than the others in increasing actinorhodin Production. Two of the identified regulatory elements occurred upstream of gene SCO5812, deletion of which reduced actinorhodin Production, confirming that experimental analysis of regulatory motifs can provide new insights into factors influencing Antibiotic Production in streptomycetes.
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EshA accentuates ppGpp accumulation and is conditionally required for Antibiotic Production in Streptomyces coelicolor A3(2).
Journal of bacteriology, 2006Co-Authors: Natsumi Saito, Takeshi Hosaka, Susumu Okamoto, Mervyn J. Bibb, Hiroyuki Aoki, Kozo OchiAbstract:Disruption of eshA, which encodes a 52-kDa protein that is produced late during the growth of Streptomyces coelicolor A3(2), resulted in elimination of actinorhodin Production. In contrast, disruption of eshB, a close homologue of eshA, had no effect on Antibiotic Production. The eshA disruptant accumulated lower levels of ppGpp than the wild-type strain accumulated. The loss of actinorhodin Production in the eshA disruptant was restored by expression of a truncated relA gene, which increased the ppGpp level to the level in the wild-type strain, indicating that the reduced ppGpp accumulation in the eshA mutant was solely responsible for the loss of Antibiotic Production. Antibiotic Production was also restored in the eshA mutant by introducing mutations into rpoB (encoding the RNA polymerase β subunit) that bypassed the requirement for ppGpp, which is consistent with a role for EshA in modulating ppGpp levels. EshA contains a cyclic nucleotide-binding domain that is essential for its role in triggering actinorhodin Production. EshA may provide new insights and opportunities to unravel the molecular signaling events that occur during physiological differentiation in streptomycetes.
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engineering of primary carbon metabolism for improved Antibiotic Production in streptomyces lividans
Applied and Environmental Microbiology, 2002Co-Authors: Michael J Butler, P Bruheim, S Jovetic, Flavia Marinelli, P W Postma, Mervyn J. BibbAbstract:Deletions were made in Streptomyces lividans in either of two genes (zwf1 and zwf2) encoding isozymes of glucose-6-phosphate dehydrogenase, the first enzyme in the oxidative pentose phosphate pathway (PPP). Each mutation reduced the level of Zwf activity to approximately one-half that observed in the wild-type strain. When the mutants were transformed with multicopy plasmids carrying the pathway-specific transcriptional activator genes for either the actinorhodin (ACT) or undecylprodigiosin (RED) biosynthetic pathway, they produced higher levels of Antibiotic than the corresponding wild-type control strains. The presumed lower flux of carbon through the PPP in each of the Δzwf mutants may allow more efficient glucose utilization via glycolysis, resulting in higher levels of Antibiotic Production. This appears to occur without lowering the concentration of NADPH (the major biochemical product of the oxidative PPP activity) to a level that would limit Antibiotic biosynthesis. Consistent with this hypothesis, deletion of the gene (devB) encoding the enzyme that catalyzes the next step in the oxidative PPP (6-phosphogluconolactonase) also resulted in increased Antibiotic Production. However, deletion of both zwf genes from the devB mutant resulted in reduced levels of ACT and RED Production, suggesting that some of the NADPH made by the PPP is utilized, directly or indirectly, for Antibiotic biosynthesis. Although applied here to the model Antibiotics ACT and RED, such mutations may prove to be useful for improving the yield of commercially important secondary metabolites.
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afsR is a pleiotropic but conditionally required regulatory gene for Antibiotic Production in Streptomyces coelicolor A3(2)
Molecular microbiology, 1996Co-Authors: Belén Floriano, Mervyn J. BibbAbstract:The N-terminal region of AfsR, a putative pleiotropic regulatory protein for Antibiotic Production in Strepto-myces coelicolor A3(2), is homologous to RedD and ActII-ORF4, pathway-specific regulatory proteins required for the Production of the Antibiotics undecylprodigiosin (Red) and actinorhodin (Act), respectively. The recent identification of afsS, which lies immediately 3′ of afsR and which stimulates Antibiotic Production when cloned at high copy number, questioned whether afsR was a pleiotropic regulatory gene. In this study we demonstrate that multiple copies of afsR can stimulate both Act and Red Production and that, despite its homology, it cannot substitute for the pathway-specific regulatory genes. Moreover, an in-frame deletion that removed most of the afsR coding sequence resulted in loss of Act and Red Production, and a marked reduction in the synthesis of the calcium-dependent Antibiotic (CDA), but only under some (non-permissive) nutritional conditions. Although additional copies of afsR resulted in elevated levels of the actII-ORF4 and redD transcripts, transcription of the pathway-specific regulatory genes under non-permissive conditions was unaffected by deletion of afsR. While afsR may operate independently of the pathway-specific regulatory proteins to influence Antibiotic Production, the activity of ActII-ORF4 and of RedD under non-permissive conditions could depend on interaction with, or modification by, AfsR.
Guojun Wang - One of the best experts on this subject based on the ideXlab platform.
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The G243D mutation (afsB mutation) in the principal sigma factor σHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2)
Microbiology, 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor σ HrdB. Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB+ parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.
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The G243D mutation (afsB mutation) in the principal sigma factor sigmaHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2).
Microbiology (Reading England), 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor sigma(HrdB). Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB(+) parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.
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dramatic activation of Antibiotic Production in streptomyces coelicolor by cumulative drug resistance mutations
Applied and Environmental Microbiology, 2008Co-Authors: Guojun Wang, Takeshi Hosaka, Kozo OchiAbstract:We recently described a new method to activate Antibiotic Production in bacteria by introducing a mutation conferring resistance to a drug such as streptomycin, rifampin, paromomycin, or gentamicin. This method, however, enhanced Antibiotic Production by only up to an order of magnitude. Working with Streptomyces coelicolor A3(2), we established a method for the dramatic activation of Antibiotic Production by the sequential introduction of multiple drug resistance mutations. Septuple and octuple mutants, C7 and C8, thus obtained by screening for resistance to seven or eight drugs, produced huge amounts (1.63 g/liter) of the polyketide Antibiotic actinorhodin, 180-fold higher than the level produced by the wild type. This dramatic overProduction was due to the acquisition of mutant ribosomes, with aberrant protein and ppGpp synthesis activity, as demonstrated by in vitro protein synthesis assays and by the abolition of Antibiotic overProduction with relA disruption. This new approach, called "ribosome engineering," requires less time, cost, and labor than other methods and may be widely utilized for bacterial strain improvement.
Nuran Deveci - One of the best experts on this subject based on the ideXlab platform.
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Anaerobic Treatment of Antibiotic Production Wastewater and Kinetic Evaluations
Journal of Biochemistry, 2004Co-Authors: Ilda Degirmentas, Nuran DeveciAbstract:In this study, the anaerobic treatment of high-strength Antibiotic Production wastewater and the development of a mathematical model for the treatment were attempted. Anaerobic treatability was investigated using synthetic solutions and original wastewater of which the initial chemical oxygen demand (COD) was determined. Initial COD of solutions was increased from 3,000 to 43,000 mg O 2 /liter in an anaerobic bioreactor. The bioreactor pH was maintained at 6.5-7.5. The temperature was kept constant at 37 ′ 1°C. Raw materials and original wastewater containing penicillin Antibiotics were obtained from Fako Pharmaceutical Factory (Fako) in Istanbul, Turkey. Anaerobic sludge used for treatment was obtained from Pakmaya Baker's Yeast Producing Factory (Pakmaya) in Izmit, Turkey and the Fako. A mathematical model based on substrate (total COD) concentration was developed assuming that only three consecutive reactions, namely, hydrolysis, acidogenesis and methano-genesis, are significant. From the experimental data, a model that can be used for COD calculation as a function of time was developed using the first- and the second-order kinetic approaches. Making use of the developed model equation, it was proved that the anaerobic treatment of high strength (COD > 25,000 mg O 2 /liter) Antibiotic Production wastewater fits the second-order kinetics.
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Anaerobic treatment of Antibiotic Production wastewater and kinetic evaluations.
Journal of biochemistry, 2004Co-Authors: Ilda Degirmentas, Nuran DeveciAbstract:In this study, the anaerobic treatment of high-strength Antibiotic Production wastewater and the development of a mathematical model for the treatment were attempted. Anaerobic treatability was investigated using synthetic solutions and original wastewater of which the initial chemical oxygen demand (COD) was determined. Initial COD of solutions was increased from 3,000 to 43,000 mg O(2)/liter in an anaerobic bioreactor. The bioreactor pH was maintained at 6.5-7.5. The temperature was kept constant at 37 +/- 1 degrees C. Raw materials and original wastewater containing penicillin Antibiotics were obtained from Fako Pharmaceutical Factory (Fako) in Istanbul, Turkey. Anaerobic sludge used for treatment was obtained from Pakmaya Baker's Yeast Producing Factory (Pakmaya) in Izmit, Turkey and the Fako. A mathematical model based on substrate (total COD) concentration was developed assuming that only three consecutive reactions, namely, hydrolysis, acidogenesis and methanogenesis, are significant. From the experimental data, a model that can be used for COD calculation as a function of time was developed using the first- and the second-order kinetic approaches. Making use of the developed model equation, it was proved that the anaerobic treatment of high strength (COD > 25,000 mg O(2)/liter) Antibiotic Production wastewater fits the second-order kinetics.
Yukinori Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Metabolic perturbation to enhance polyketide and nonribosomal peptide Antibiotic Production using triclosan and ribosome-targeting drugs
Applied Microbiology and Biotechnology, 2017Co-Authors: Yukinori Tanaka, Masumi Izawa, Yoshikazu Hiraga, Yuya Misaki, Tomoko Watanabe, Kozo OchiAbstract:Although transcriptional activation of pathwayspecific positive regulatory genes and/or biosynthetic genes is primarily important for enhancing secondary metabolite Production, reinforcement of substrate supply, as represented by primary metabolites, is also effective. For example, partial inhibition of fatty acid synthesis with ARC2 (an analog of triclosan) was found to enhance polyketide Antibiotic Production. Here, we demonstrate that this approach is effective even for industrial high-producing strains, for example enhancing salinomycin Production by 40%, reaching 30.4 g/l of salinomycin in an industrial Streptomyces albus strain. We also hypothesized that a similar approach would be applicable to another important Antibiotic group, nonribosomal peptide (NRP) Antibiotics. We therefore attempted to partially inhibit protein synthesis by using ribosome-targeting drugs at subinhibitory concentrations (1/50∼1/2 of MICs), which may result in the preferential recruitment of intracellular amino acids to the biosynthesis of NRP Antibiotics rather than to protein synthesis. Among the ribosome-targeting drugs examined, chloramphenicol at subinhibitory concentrations was most effective at enhancing the Production by Streptomyces of NRP Antibiotics such as actinomycin, calcium-dependent Antibiotic (CDA), and piperidamycin, often resulting in an almost 2-fold increase in Antibiotic Production. Chloramphenicol activated biosynthetic genes at the transcriptional level and increased amino acid pool sizes 1.5- to 6-fold, enhancing the Production of actinomycin and CDA. This “metabolic perturbation” approach using subinhibitory concentrations of ribosome-targeting drugs is a rational method of enhancing NRP Antibiotic Production, being especially effective in transcriptionally activated (e.g., rpoB mutant) strains. Because this approach does not require prior genetic information, it may be widely applicable for enhancing bacterial Production of NRP Antibiotics and bioactive peptides.
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Improved Antibiotic Production and silent gene activation in Streptomyces diastatochromogenes by ribosome engineering.
The Journal of antibiotics, 2015Co-Authors: Xuping Shentu, Liu Nannan, Yukinori Tanaka, Kozo OchiAbstract:Improved Antibiotic Production and silent gene activation in Streptomyces diastatochromogenes by ribosome engineering
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The G243D mutation (afsB mutation) in the principal sigma factor σHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2)
Microbiology, 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor σ HrdB. Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB+ parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.
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The G243D mutation (afsB mutation) in the principal sigma factor sigmaHrdB alters intracellular ppGpp level and Antibiotic Production in Streptomyces coelicolor A3(2).
Microbiology (Reading England), 2010Co-Authors: Guojun Wang, Yukinori Tanaka, Kozo OchiAbstract:Deficient Antibiotic Production in an afsB mutant, BH5, of Streptomyces coelicolor A3(2) was recently shown to be due to a mutation (G243D) in region 1.2 of the primary sigma factor sigma(HrdB). Here we show that intracellular ppGpp levels during growth, as well as after amino acid depletion, in the mutant BH5 are lower than those of the afsB(+) parent strain. The introduction of certain rifampicin resistance (rif) mutations, which bypassed the requirement of ppGpp for transcription of pathway-specific regulatory genes, actII-ORF4 and redD, for actinorhodin and undecylprodigiosin, respectively, completely restored Antibiotic Production by BH5. Antibiotic Production was restored also by introduction of a new class of thiostrepton-resistance (tsp) mutations, which provoked aberrant accumulation of intracellular ppGpp. Abolition of ppGpp synthesis in the afsB tsp mutant Tsp33 again abolished Antibiotic Production. These results indicate that intracellular ppGpp level is finely tuned for successful triggering of Antibiotic Production in the wild-type strain, and that this fine tuning was absent from the afsB mutant BH5, resulting in a failure to initiate Antibiotic Production in this strain.