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CHICAGO, IL, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 491.48K | Year: 2008

DESCRIPTION (provided by applicant): Industrial metabolic engineering is a method for performing strain improvement in industrial microorganisms by harnessing the power of random in vitro transposition mutagenesis. The organisms we aim to improve in this s tudy are the actinomycetes, a group of soil bacteria that are best known for their ability to produce over two thirds of the worlds naturally derived antibiotics, anticancer agents, and immunosuppressants currently in medical use. The transposon tagging pr ocess is powerful not only because of its ability to make strain improvement mutations, but also because it allows strains to be easily reverse engineered to reveal the identity of the affected gene. Once the strain improvement target is identified, new ge netic and metabolic knowledge is revealed that can lead to further optimization and extension of the technology to other organisms of medical importance. The model organism used in this study is the erythromycin producing organism, Saccharopolyspora erythr aea, a bacterium that has been the subject of over 50 years of intensive genetic and biochemical research, providing a solid foundation upon which to build the fundamentals for the emerging field of metabolic engineering of industrial microorganisms.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 210.63K | Year: 2007

DESCRIPTION (provided by applicant): A type of metabolic engineering described in this proposal, and referred to as "industrial" metabolic engineering, is a method for performing strain improvement in industrial microorganisms by harnessing the power of in vitro transposition mutagenesis. The industrial microorganisms of interest to this study are the actinomycetes, a group of soil bacteria that are best known for their ability to produce over two thirds of the worlds naturally derived antibiotics, anticancer agents, and immunosuppressants currently in medical use. Industrial metabolic engineering also benefits from technical progress made in microfermentation screening. Microfermentations make possible the economical screening of large numbers of mutants in order find improved strains. Because of the transposon tagging process, these improved mutants can be easily reverse engineered to reveal the identity of the strain improvement mutation they harbor in their genome. Once the strain improvement target is identified, new genetic and metabolic knowledge is revealed that can lead to further optimization of the technology and extension of the technology to other industrial fermentation processes of medical importance. The model organism used in this study is the erythromycin producing organism, S. erythraea, that has been the subject of over 50 years of intensive genetic and biochemical research, providing a solid foundation upon which to build the fundamentals for the emerging field of predictive metabolic engineering of industrial microorganisms. 1 PROJECTNARRATIVE Industrial Metabolic Engineering Metabolic engineering will someday give scientists the ability to predicatively manipulate biological organisms for many useful purposes ranging from strain improvement and other industrial biotech applications, to allowing greater agricultural production, permitting more efficient and safer energy production, and providing better understanding of the metabolic basis for medical conditions that will assist in the development of new cures. For some promising new natural products, our technology could make the difference between a drug making it to market, or being abandoned due to inadequate supply of the drug for testing or commercial distribution.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 380.42K | Year: 2007

DESCRIPTION (provided by applicant): Fermalogic recently discovered that the key erythromycin precursor, methylmalonyl- CoA, is the limiting factor for improved erythromycin production. As such, the methylmalonyl-CoA metabolic node has become a focal point for strain improvement strategies. The main goals of this study are to identify key enzymes and metabolic pathways either known or predicted to affect carbon flow at the methylmalonyl-CoA node and manipulate these genes and pathways for increased erythromycin production. Many other natural products besides erythromycin are made from methylmalonyl-CoA precursors, therefore the information gained from this study could be applicable to a broad range of pharmaceutical compounds including other antibiotics, anti-cancer com- pounds, and immunosuppressants. For the last fifty years strain improvement has been performed by a random mutate-and-screen process that has not generated any information regarding the genetics or biochemistry of strain improvement. This study will pro- vide important information and technology that can be used to rationally engineer Actinomycetes for rapid commercial development of critically needed new natural products, and to improve the production of existing products to reduce the cost of production. Metabolic engineering has as its primary goal the rational application of genetic and biochemical data for the improvement of a production process. The ability to identify important genes, enzymes, and metabolic pathways for an important production process will allow metabolic engineers to impart rational manipulations to the producing strain for improved production. These applications will have far-reaching effects in disciplines such as pharmaceutical production, agriculture, and many other biotechnology applications. The technology that will be developed in this project will elucidate path- ways leading to the biosynthesis of commercially important antibiotics with a focus on erythromycin.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 237.82K | Year: 2009

DESCRIPTION (provided by applicant): Knowledge of amino acid metabolism is critical to human health and has significant industrial applications as well. This study proposes to develop a coproduct method for the production of L-lysine, an essential amino acid of great economic and industrial importance. If successful, the L-lysine produced as a result of this study will be a coproduct of the erythromycin fermentation using Saccharopolyspora erythraea. Currently, L-lysine is produced from dedicated Corynebactium glutamicum fermentations, and as such, has costs associated with its production that are not absorbed through the production of a primary fermentation product. L-lysine produced as a coproduct from the erythromycin fermentation would be substantially less expensive to produce, and large quantities could be produced using this method because the erythromycin fermentation is also a very large-scale process. In addition, this study also proposes to investigate the potential for developing a dedicated fermentation method for L-cysteine production, using an erythromycin non-producing variant of S. erythraea. Until recently there was no need for fermentation-produced L-cysteine; but due to recent government regulations against the use of animal derived L-cysteine, the market for fermentation-produced material has grown significantly. The model organism used in this study is the erythromycin producing organism, S. erythraea, a bacterium that has been the subject of over 50 years of intensive genetic and biochemical research, providing a solid foundation upon which to build commercial processes for amino acid production. Public Health Relevance: Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a family of rare progressive neurodegenerative disorders that affect both humans and animals. Prion diseases are usually rapidly progressive and always fatal. This project aims to reduce the risk of acquiring TSElts in the population through the development of a biotechnological process for the production of amino acids that are used by humans and are currently obtained from possibly contaminated animal sources.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 404.33K | Year: 2005

DESCRIPTION (provided by applicant): Rapamycin (sirolimus) has recently been approved for clinical use in transplantation medicine and improved derivatives are already under development. Rapamycin also has potential as an anti-cancer therapeutic, therefore the market for this compound is expanding rapidly. The current problem is that the rapamycin-producing organism, Streptomyces hygroscopicus, has not been improved significantly from the wild-type level, and therefore is extremely inefficient at producing this natural product. Rapamycin is very expensive to produce, which is reflected in the high cost of therapy with this drug. We propose a straightforward rational strain improvement strategy that if successful will bring the fermentation process up to a commercially acceptable production level. The approach involves metabolic engineering of two important precursor feeding pathways. Fermalogic has recently demonstrated the success of this strategy by increasing the production of the macrolide antibiotic, erythromycin. This will be the first test of this technology for a drug other than erythromycin, and will help to establish the general applicability of the strategy for strain improvement.

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