Vancomycin production in batch and continuous culture

McIntyre, Justyna; Bull, Alan T.; Bunch, Alan William

doi:10.1002/(sici)1097-0290(19960220)49:4<412::aid-bit8>3.0.co;2-s

Cited by 44 publications

(32 citation statements)

References 31 publications

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“…Mutations in the rpoB gene were determined by DNA sequencing using the primers listed in Table S1 in the supplemental material. Strains were grown in GYM medium (21), SPY medium (21), SYM medium (21), MPY medium (22), R4 medium (23), R3/1 medium (24), or vancomycin production medium (25) at 25°C or 30°C under rotary shaking (220 rpm) as described in the text. All measurements for antibiotic productivity were performed in triplicate or more flasks, and the antibiotic titers were expressed as means Ϯ standard deviations (SD).…”

Section: Methodsmentioning

confidence: 99%

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Tanaka

Kasahara²,

Hirose³

et al. 2013

J Bacteriol

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A subset of rifampin resistance (rpoB) mutations result in the overproduction of antibiotics in various actinomycetes, including Streptomyces, Saccharopolyspora, and Amycolatopsis, with H437Y and H437R rpoB mutations effective most frequently. Moreover, the rpoB mutations markedly activate (up to 70-fold at the transcriptional level) the cryptic/silent secondary metabolite biosynthetic gene clusters of these actinomycetes, which are not activated under general stressful conditions, with the exception of treatment with rare earth elements. Analysis of the metabolite profile demonstrated that the rpoB mutants produced many metabolites, which were not detected in the wild-type strains. This approach utilizing rifampin resistance mutations is characterized by its feasibility and potential scalability to high-throughput studies and would be useful to activate and to enhance the yields of metabolites for discovery and biochemical characterization. Actinomycetes produce a variety of natural products that are of major importance in the pharmaceutical industry. More than 50% of all anti-infective and anticancer compounds developed over the past 25 years have been natural products or derivatives thereof (1). Discovery of novel antibiotics and strain improvement for overproduction are important in applied microbiology research, especially in the production of clinically important antibiotics as well as antibiotics important in veterinary medicine and agriculture. There is accumulating evidence that the ability of actinomycetes to produce antibiotics and other bioactive secondary metabolites has been underestimated due to the presence of cryptic gene clusters. That is, genome sequencing projects have revealed many biosynthetic gene clusters for the production of unknown secondary metabolites. For example, Streptomyces coelicolor, Streptomyces avermitilis, Streptomyces griseus, and Saccharopolyspora erythraea are each known to produce three to five secondary metabolites but actually possess Ͼ20 clusters that encode known or predicted biosynthetic pathways for secondary metabolites (2-5). Exploitation of such genetic potential in actinomycetes may lead to the isolation of new biologically active compounds (6-8). We recently described a new method to increase antibiotic production in bacteria by modulating ribosomal components (ribosomal proteins or rRNA), i.e., by introducing mutations conferring drug resistance, as many antibiotics target the ribosome (9-11). This new approach, called "ribosome engineering" (12, 13), has several advantages, including the ability to screen for drug resistance mutations by simple selection on drugcontaining plates, even if the mutation frequency is extremely low (e.g., Ͻ10 Ϫ10 ), and the ability to select for mutations without prior genetic information. Hence, this method requires no induced mutagenesis. Interestingly, the introduction of several drug resistance mutations has a cumulative effect on antibiotic production (14-16).In addition to enhancement of antibiotic production, we have demon...

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Section: Methodsmentioning

confidence: 99%

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Tanaka

Kasahara²,

Hirose³

et al. 2013

J Bacteriol

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“…The inoculated cultures are grown on a medium containing 5% glucose, 10% soluble starch, 5% peptone, and 5% yeast extract at pH 6.7. Vancomycin is produced in 250 ml flasks containing 40 mL of culture medium (20 g L −1 glucose/sucrose, 5 g L −1 peptone, 0.75 g l −1 MgSO 4 · 6H 2 O, 1 g L −1 NaCl, 0.5 g L −1 KCl, 10 g L −1 trace metal solution and 10 g L −1 3-(N-morpholino)propanesulfonic acid) pH 6.7, using a 5% inoculum and incubating at 30 °C in an orbital shaker at 3.7 rps for 96−120 h (McIntyre et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

“…Vancomycin, which is a glycopeptide antibiotic along with N-dimethylvancomycin that is produced by the actinomycete Amycolatopsis orientalis (McIntyre et al, 1996), was chosen as the active ingredient for this case study. Adsorption of vancomycin was studied using different adsorbents.…”

Section: Introductionmentioning

confidence: 99%

Comparison of adsorption equilibrium and kinetic models for a case study of pharmaceutical active ingredient adsorption from fermentation broths: parameter determination, simulation, sensitivity analysis and optimization

Likozar

Senica²,

Pavko³

2012

Braz. J. Chem. Eng.

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-Mathematical models for a batch process were developed to predict concentration distributions for an active ingredient (vancomycin) adsorption on a representative hydrophobic-molecule adsorbent, using differently diluted crude fermentation broth with cells as the feedstock. The kinetic parameters were estimated using the maximization of the coefficient of determination by a heuristic algorithm. The parameters were estimated for each fermentation broth concentration using four concentration distributions at initial vancomycin concentrations of 4.96, 1.17, 2.78, and 5.54 g l −1 . In sequence, the models and their parameters were validated for fermentation broth concentrations of 0, 20, 50, and 100% (v/v) by calculating the coefficient of determination for each concentration distribution at the corresponding initial concentration. The applicability of the validated models for process optimization was investigated by using the models as process simulators to optimize the two process efficiencies.

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“…Aerial mycelia (or spores) of each glycopeptide-producing strain of interest (Amycolatopsis species MJM2582, Amycolatopsis lurida, Streptomyces toyocaensis, and Amycolatopsis balhimycina) (see Table S1 in the supplemental material) were prepared from 7-day cultures on soy flour-mannitol (SFM) agar or BN agar at 30°C (see Table S2 in the supplemental material). MJM2582 was tested for preparative glycopeptide production in media previously reported for the production of A47934 (26), teicoplanin (27), vancomycin (28), and ristocetin (29). Bioassays using S. coelicolor ⌬femX and S. coelicolor ⌬vanRS mutant strains showed that the only medium that reliably yielded glycopeptides was Streptomyces antibiotic medium (SAM), used for A47934 biosynthesis (26).…”

Section: Methodsmentioning

confidence: 99%

Antibiotic Resistance Mechanisms Inform Discovery: Identification and Characterization of a Novel Amycolatopsis Strain Producing Ristocetin

Truman

Kwun

Cheng

et al. 2014

Antimicrob Agents Chemother

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dDiscovering new antibiotics is a major scientific challenge, made increasingly urgent by the continued development of resistance in bacterial pathogens. A fundamental understanding of the mechanisms of bacterial antibiotic resistance will be vital for the future discovery or design of new, more effective antibiotics. We have exploited our intimate knowledge of the molecular mechanism of glycopeptide antibiotic resistance in the harmless bacterium Streptomyces coelicolor to develop a new two-step cell wall bioactivity screen, which efficiently identified a new actinomycete strain containing a previously uncharacterized glycopeptide biosynthetic gene cluster. The screen first identifies natural product extracts capable of triggering a generalized cell wall stress response and then specifically selects for glycopeptide antibacterials by assaying for the induction of glycopeptide resistance genes. In this study, we established a diverse natural product extract library from actinomycete strains isolated from locations with widely varying climates and ecologies, and we screened them using the novel two-step bioassay system. The bioassay ultimately identified a single strain harboring the previously unidentified biosynthetic gene cluster for the glycopeptide ristocetin, providing a proof of principle for the effectiveness of the screen. This is the first report of the ristocetin biosynthetic gene cluster, which is predicted to include some interesting and previously uncharacterized enzymes. By focusing on screening libraries of microbial extracts, this strategy provides the certainty that identified producer strains are competent for growth and biosynthesis of the detected glycopeptide under laboratory conditions.

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Vancomycin production in batch and continuous culture

Cited by 44 publications

References 31 publications

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Comparison of adsorption equilibrium and kinetic models for a case study of pharmaceutical active ingredient adsorption from fermentation broths: parameter determination, simulation, sensitivity analysis and optimization

Antibiotic Resistance Mechanisms Inform Discovery: Identification and Characterization of a Novel Amycolatopsis Strain Producing Ristocetin

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