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1.
Metabolite induction via microorganism co-culture: A potential way to enhance chemical diversity for drug discovery 总被引:1,自引:0,他引:1
Samuel Bertrand Nadine Bohni Sylvain Schnee Olivier Schumpp Katia Gindro Jean-Luc Wolfender 《Biotechnology advances》2014
Microorganisms have a long track record as important sources of novel bioactive natural products, particularly in the field of drug discovery. While microbes have been shown to biosynthesize a wide array of molecules, recent advances in genome sequencing have revealed that such organisms have the potential to yield even more structurally diverse secondary metabolites. Thus, many microbial gene clusters may be silent under standard laboratory growth conditions. In the last ten years, several methods have been developed to aid in the activation of these cryptic biosynthetic pathways. In addition to the techniques that demand prior knowledge of the genome sequences of the studied microorganisms, several genome sequence-independent tools have been developed. One of these approaches is microorganism co-culture, involving the cultivation of two or more microorganisms in the same confined environment. Microorganism co-culture is inspired by the natural microbe communities that are omnipresent in nature. Within these communities, microbes interact through signaling or defense molecules. Such compounds, produced dynamically, are of potential interest as new leads for drug discovery. Microorganism co-culture can be achieved in either solid or liquid media and has recently been used increasingly extensively to study natural interactions and discover new bioactive metabolites. Because of the complexity of microbial extracts, advanced analytical methods (e.g., mass spectrometry methods and metabolomics) are key for the successful detection and identification of co-culture-induced metabolites. 相似文献
2.
Gerard D. Wright 《Microbial biotechnology》2019,12(1):55-57
The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery. 相似文献
3.
Xueting Liu Caixia Chen Wenni He Pei Huang Miaomiao Liu Qian Wang Hui Guo Krishna Bolla Yan Lu Fuhang Song Huanqin Dai Mei Liu Lixin Zhang 《Antonie van Leeuwenhoek》2012,102(3):447-461
Multidrug-resistant tuberculosis (MDR-TB) and TB–HIV co-infection have become a great threat to global health. However, the last truly novel drug that was approved for the treatment of TB was discovered 40?years ago. The search for new effective drugs against TB has never been more intensive. Natural products derived from microbes and medicinal plants have been an important source of TB therapeutics. Recent advances have been made to accelerate the discovery rate of novel TB drugs including diversifying strategies for environmental strains, high-throughput screening (HTS) assays, and chemical diversity. This review will discuss the challenges of finding novel natural products with anti-TB activity from marine microbes and plant medicines, including biodiversity- and taxonomy-guided microbial natural products library construction, target- and cell-based HTS, and bioassay-directed isolation of anti-TB substances from traditional medicines. 相似文献
4.
Murillo L. Bution Gustavo Molina Meissa R.E. Abrahão Gláucia M. Pastore 《Critical reviews in biotechnology》2015,35(3):313-325
Throughout human history, natural products have been the basis for the discovery and development of therapeutics, cosmetic and food compounds used in industry. Many compounds found in natural organisms are rather difficult to chemically synthesize and to extract in large amounts, and in this respect, genetic and metabolic engineering are playing an increasingly important role in the production of these compounds, such as new terpenes and terpenoids, which may potentially be used to create aromas in industry. Terpenes belong to the largest class of natural compounds, are produced by all living organisms and play a fundamental role in human nutrition, cosmetics and medicine. Recent advances in systems biology and synthetic biology are allowing us to perform metabolic engineering at the whole-cell level, thus enabling the optimal design of microorganisms for the efficient production of drugs, cosmetic and food additives. This review describes the recent advances made in the genetic and metabolic engineering of the terpenes pathway with a particular focus on systems biotechnology. 相似文献
5.
6.
Natural product discovery: past,present, and future 总被引:1,自引:0,他引:1
Leonard Katz Richard H. Baltz 《Journal of industrial microbiology & biotechnology》2016,43(2-3):155-176
7.
Koehn FE 《Current opinion in biotechnology》2006,17(6):631-637
Modern drug discovery embraces a strategy of targeting cellular signal transduction pathways as a means of finding new therapeutic agents. Historically, natural products derived from microorganisms have played an important role as drug leads and clinical candidates under this paradigm. The future drug potential of natural products as signal transduction agents looks promising, as illustrated by two key examples. First, substantial advances have been made in the development of inhibitors based on immunophilin ligand polyketides, which target the TOR-mediated pathways and can modulate processes including cell proliferation and cell-cycle arrest. Second, the discovery of natural product inhibitors of the ubiquitin-proteasome proteolytic signal transduction pathway represents an emerging field. Given these examples, together with the diversity of as yet undiscovered agents, natural product signal transduction agents offer great potential for future drug discovery efforts. 相似文献
8.
James S. Miller 《Economic botany》2011,65(4):396-407
The Discovery of Medicines from Plants: A Current Biological Perspective. The last 50 years have seen tremendous innovations in the process of discovering novel bioactive compounds from plants. Every
stage of the natural products discovery and development pipeline has seen major advances, so as a result, today it is possible
to evaluate large numbers of plant extracts efficiently and in more effective ways against a wider array of disease targets.
Despite all of these technological advances and numerous large-scale discovery efforts, the number of new drugs developed
as natural products from plants to reach the market has been surprisingly low, very different from the continuing productive
discovery work from microbes. The innovations in the discovery process are reviewed, possible explanations for low success
of recent discovery efforts are explored, and an effort is made to estimate the future potential of plants as a discovery
resource. It may be that the low rate of discovery during this developmental period of natural products discovery is a consequence
of technological limitations of the discovery process rather than a lack of interesting compounds in plants, and that even
when necessary assumptions are taken into account, conservative estimates would indicate great potential for the discovery
of new drugs from plants. 相似文献
9.
Natural products as a screening resource 总被引:1,自引:0,他引:1
Harvey AL 《Current opinion in chemical biology》2007,11(5):480-484
Natural products have been the most productive source of leads for new drugs, but they are currently out of fashion with the pharmaceutical industry. New approaches to sourcing novel compounds from untapped areas of biodiversity coupled with the technical advances in analytical techniques (such as microcoil NMR and linked LC-MS-NMR) have removed many of the difficulties in using natural products in screening campaigns. As the 'chemical space' occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections, synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds. A renaissance of drug discovery inspired by natural products can be predicted. 相似文献
10.
Potential natural product discovery from microbes through a diversity-guided computational framework
Eakasit Pacharawongsakda Sunai Yokwai Supawadee Ingsriswang 《Applied microbiology and biotechnology》2009,82(3):579-586
As the occurrence of natural compounds is related to the spatial distribution and evolution of microorganisms for biological
and ecological relevance, the data integration of chemistry, geography, and phylogeny within an analytical framework is needed
to make better decisions on sourcing the microbes for drug discovery. Such a framework should help researcher to decide on
(a) which microorganisms are capable to produce the structurally diverse-bioactive compounds and (b) where those microbes
could be found. Here, we present GIST (Geospatial Integrated Species, sites and bioactive compound relationships Tracking
tool), a computational framework that could describe and compare how the chemical and genetic diversity varied among microbes
in different areas. GIST mainly exploits the measures of bioactive diversity (BD) and phylogenetic diversity (PD), derived
from the branch length of bioactive dendrogram and phylogenetic tree, respectively. Based on BD and PD, our framework could
provide guidance and tools for measuring, monitoring, and evaluating of patterns and changes in biodiversity of microorganisms
to improve the success rate of drug discovery.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
11.
O. Prakash M. Verma P. Sharma M. Kumar K. Kumari A. Singh H. Kumari S. Jit S. K. Gupta M. Khanna R. Lal 《Indian journal of microbiology》2007,47(2):98-108
Classification of microorganisms on the basis of traditional microbiological methods (morphological, physiological and biochemical)
creates a blurred image about their taxonomic status and thus needs further clarification. It should be based on a more pragmatic
approach of deploying a number of methods for the complete characterization of microbes. Hence, the methods now employed for
bacterial systematics include, the complete 16S rRNA gene sequencing and its comparative analysis by phylogenetic trees, DNA-DNA
hybridization studies with related organisms, analyses of molecular markers and signature pattern(s), biochemical assays,
physiological and morphological tests. Collectively these genotypic, chemotaxonomic and phenotypic methods for determining
taxonomic position of microbes constitute what is known as the ‘polyphasic approach’ for bacterial systematics. This approach
is currently the most popular choice for classifying bacteria and several microbes, which were previously placed under invalid
taxa have now been resolved into new genera and species. This has been possible owing to rapid development in molecular biological
techniques, automation of DNA sequencing coupled with advances in bioinformatic tools and access to sequence databases. Several
DNA-based typing methods are known; these provide information for delineating bacteria into different genera and species and
have the potential to resolve differences among the strains of a species. Therefore, newly isolated strains must be classified
on the basis of the polyphasic approach. Also previously classified organisms, as and when required, can be reclassified on
this ground in order to obtain information about their accurate position in the microbial world. Thus, current techniques
enable microbiologists to decipher the natural phylogenetic relationships between microbes. 相似文献
12.
In the highly competitive environment of contemporary pharmaceutical research, natural products provide a unique element of molecular diversity and biological functionality which is indispensable for drug discovery. The emergence of strategies to deliver drug leads from natural products within the same time frame as synthetic chemical screening has eliminated a major limitation of the past. At a more functional level, the application of molecular genetics techniques has permitted the manipulation of biosynthetic pathways for the generation of novel chemical species as well as rendering hitherto uncultivatable microorganisms accessible for secondary metabolite generation. These developments augur well for an industry confronted with the challenge of finding lead compounds directed at the plethora of new targets arising from genomics projects. The exploitation of structural chemical databases comprising a wide variety of chemotypes, in conjunction with databases on target genes and proteins, will facilitate the creation of new chemical entities through computational molecular modelling for pharmacological evaluation. 相似文献
13.
Arnold L. Demain 《Journal of industrial microbiology & biotechnology》2014,41(2):185-201
Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic. 相似文献
14.
Search and discovery strategies for biotechnology: the paradigm shift. 总被引:21,自引:0,他引:21
Profound changes are occurring in the strategies that biotechnology-based industries are deploying in the search for exploitable biology and to discover new products and develop new or improved processes. The advances that have been made in the past decade in areas such as combinatorial chemistry, combinatorial biosynthesis, metabolic pathway engineering, gene shuffling, and directed evolution of proteins have caused some companies to consider withdrawing from natural product screening. In this review we examine the paradigm shift from traditional biology to bioinformatics that is revolutionizing exploitable biology. We conclude that the reinvigorated means of detecting novel organisms, novel chemical structures, and novel biocatalytic activities will ensure that natural products will continue to be a primary resource for biotechnology. The paradigm shift has been driven by a convergence of complementary technologies, exemplified by DNA sequencing and amplification, genome sequencing and annotation, proteome analysis, and phenotypic inventorying, resulting in the establishment of huge databases that can be mined in order to generate useful knowledge such as the identity and characterization of organisms and the identity of biotechnology targets. Concurrently there have been major advances in understanding the extent of microbial diversity, how uncultured organisms might be grown, and how expression of the metabolic potential of microorganisms can be maximized. The integration of information from complementary databases presents a significant challenge. Such integration should facilitate answers to complex questions involving sequence, biochemical, physiological, taxonomic, and ecological information of the sort posed in exploitable biology. The paradigm shift which we discuss is not absolute in the sense that it will replace established microbiology; rather, it reinforces our view that innovative microbiology is essential for releasing the potential of microbial diversity for biotechnology penetration throughout industry. Various of these issues are considered with reference to deep-sea microbiology and biotechnology. 相似文献
15.
Recombinant environmental libraries provide access to microbial diversity for drug discovery from natural products 总被引:18,自引:0,他引:18
Courtois S Cappellano CM Ball M Francou FX Normand P Helynck G Martinez A Kolvek SJ Hopke J Osburne MS August PR Nalin R Guérineau M Jeannin P Simonet P Pernodet JL 《Applied and environmental microbiology》2003,69(1):49-55
To further explore possible avenues for accessing microbial biodiversity for drug discovery from natural products, we constructed and screened a 5,000-clone "shotgun" environmental DNA library by using an Escherichia coli-Streptomyces lividans shuttle cosmid vector and DNA inserts from microbes derived directly (without cultivation) from soil. The library was analyzed by several means to assess diversity, genetic content, and expression of heterologous genes in both expression hosts. We found that the phylogenetic content of the DNA library was extremely diverse, representing mostly microorganisms that have not been described previously. The library was screened by PCR for sequences similar to parts of type I polyketide synthase genes and tested for the expression of new molecules by screening of live colonies and cell extracts. The results revealed new polyketide synthase genes in at least eight clones. In addition, at least five additional clones were confirmed by high-pressure liquid chromatography analysis and/or biological activity to produce heterologous molecules. These data reinforce the idea that exploiting previously unknown or uncultivated microorganisms for the discovery of novel natural products has potential value and, most importantly, suggest a strategy for developing this technology into a realistic and effective drug discovery tool. 相似文献
16.
Recombinant Environmental Libraries Provide Access to Microbial Diversity for Drug Discovery from Natural Products 总被引:15,自引:0,他引:15 下载免费PDF全文
Sophie Courtois Carmela M. Cappellano Maria Ball Francois-Xavier Francou Philippe Normand Grard Helynck Asuncion Martinez Steven J. Kolvek Joern Hopke Marcia S. Osburne Paul R. August Renaud Nalin Michel Gurineau Pascale Jeannin Pascal Simonet Jean-Luc Pernodet 《Applied microbiology》2003,69(1):49-55
To further explore possible avenues for accessing microbial biodiversity for drug discovery from natural products, we constructed and screened a 5,000-clone “shotgun” environmental DNA library by using an Escherichia coli-Streptomyces lividans shuttle cosmid vector and DNA inserts from microbes derived directly (without cultivation) from soil. The library was analyzed by several means to assess diversity, genetic content, and expression of heterologous genes in both expression hosts. We found that the phylogenetic content of the DNA library was extremely diverse, representing mostly microorganisms that have not been described previously. The library was screened by PCR for sequences similar to parts of type I polyketide synthase genes and tested for the expression of new molecules by screening of live colonies and cell extracts. The results revealed new polyketide synthase genes in at least eight clones. In addition, at least five additional clones were confirmed by high-pressure liquid chromatography analysis and/or biological activity to produce heterologous molecules. These data reinforce the idea that exploiting previously unknown or uncultivated microorganisms for the discovery of novel natural products has potential value and, most importantly, suggest a strategy for developing this technology into a realistic and effective drug discovery tool. 相似文献
17.
Production of isoprenoid pharmaceuticals by engineered microbes 总被引:1,自引:0,他引:1
Throughout human history, natural products have been the foundation for the discovery and development of therapeutics used to treat diseases ranging from cardiovascular disease to cancer. Their chemical diversity and complexity have provided structural scaffolds for small-molecule drugs and have consistently served as inspiration for medicinal design. However, the chemical complexity of natural products also presents one of the main roadblocks for production of these pharmaceuticals on an industrial scale. Chemical synthesis of natural products is often difficult and expensive, and isolation from their natural sources is also typically low yielding. Synthetic biology and metabolic engineering offer an alternative approach that is becoming more accessible as the tools for engineering microbes are further developed. By reconstructing heterologous metabolic pathways in genetically tractable host organisms, complex natural products can be produced from inexpensive sugar starting materials through large-scale fermentation processes. In this Perspective, we discuss ongoing research aimed toward the production of terpenoid natural products in genetically engineered Escherichia coli and Saccharomyces cerevisiae. 相似文献
18.
隐性次级代谢产物生物合成基因簇的激活及天然产物定向发现 总被引:1,自引:0,他引:1
传统的"活性-化合物"天然药物发现方法导致大量已知化合物被重复分离,大大加剧了新药发现的难度。规模化基因组测序揭示了微生物基因组中存在大量的隐性(cryptic)次级代谢产物生物合成基因簇,如何激活这些隐性基因簇成为当今世界天然产物研究领域的难点与热点。本文从途径特异性和多效性两个角度综述了隐性生物合成基因簇激活策略;同时,对基因组信息指导下结构导向(structure-guided)的化合物定向分离技术进行了归纳。隐性基因簇的激活为定向发掘具有优良活性的新型天然产物提供了新的契机。 相似文献
19.
Haruo Ikeda 《Bioscience, biotechnology, and biochemistry》2017,81(1):13-22
With the decision to award the Nobel Prize in Physiology or Medicine to Drs. S. ōmura, W.C. Campbell, and Y. Tu, the importance and usefulness of natural drug discovery and development have been revalidated. Since the end of the twentieth century, many genome analyses of organisms have been conducted, and accordingly, numerous microbial genomes have been decoded. In particular, genomic studies of actinomycetes, micro-organisms that readily produce natural products, led to the discovery of biosynthetic gene clusters responsible for producing natural products. New explorations for natural products through a comprehensive approach combining genomic information with conventional methods show great promise for the discovery of new natural products and even systematic generation of unnaturally occurring compounds. 相似文献
20.
Marialuisa Menna 《Phytochemistry Reviews》2009,8(2):461-472
Ascidians, invertebrates belonging to the subphylum Urochordata (Tunicata), are renowned for their great chemical diversity,
and during the last 25 years, they have been shown to produce an array of cytotoxic molecules. Among the first six marine-derived
compounds that have reached clinical trials as antitumor agents, three are derived from ascidians, as evidence of the high
potential of these organisms as a new source of antitumor compounds. Reported in this communication are some recent results
on the chemistry of Mediterranean ascidians; a number of new molecules with different structural features but all endowed
with antiproliferative or cytotoxic activity are discussed. These results strongly evidence the highly significant role that
Mediterranean ascidians natural products could play in anticancer drug discovery and development process. 相似文献