Bioactive natural products from endophytes: a review

Endophytes, microorganisms that reside in the internal tissues of living plants without causing any immediate overt negative effects, have been found in every plant species examined to date and recognized as potential sources of novel natural products for exploitation in medicine, agriculture, and industry with more and more bioactive natural products isolated from the microorganisms. In this review, we focus mainly on bioactive natural products from endophytic microorganisms by their different functional roles. The prospect and facing problems of isolating natural products from endophytes are also discussed.     

Bioactive natural products from endophytes: A review

Endophytes, microorganisms that reside in the internal tissues of living plants without causing any immediate overt negative effects, have been found in every plant species examined to date and recognized as potential sources of novel natural products for exploitation in medicine, agriculture, and industry with more and more bioactive natural products isolated from the microorganisms. In this review, we focus mainly on bioactive natural products from endophytic microorganisms by their different functional roles. The prospect and facing problems of isolating natural products from endophytes are also discussed. Published in Russian in Prikladnaya Biokhimiya i Mikrobiologiya, 2008, Vol. 44, No. 2, pp. 153–158. The text was submitted by the authors in English.     

基于CRISPR/Cas系统的天然产物生物合成基因簇克隆和编辑技术

合成生物学和基因组测序技术的快速发展使挖掘和高效合成天然产物进入了一个全新的时代。由于多数原始菌株生长缓慢、难以培养及遗传改造困难等问题,导致天然产物生物合成基因簇的激活和高效表达受到严重制约。基于此,将原始菌株来源的基因簇转移到操作简便、遗传背景清晰的模式宿主中进行异源表达成为天然产物发现和产量提高的一种有效手段。其中,基因簇的克隆与编辑是实现天然产物异源表达的一个主要限速步骤。CRISPR/Cas技术的应用极大地提高了大型基因簇克隆和编辑的效率,有效促进了微生物来源新药的发现。本文针对基于CRISPR/Cas开发的基因簇克隆和编辑技术进行了系统梳理和全面总结,探讨相关技术在天然产物挖掘和高效合成中的应用及其重要意义。     

源于微生物的海鞘天然产物

海洋动物是具有生物活性海洋天然产物的重要来源。海鞘中含有丰富的微生物类群,如细菌、放线菌、真菌和蓝细菌。越来越多的直接或间接证据表明,一些从海鞘中分离的天然产物并不是海鞘本身产生的,而是由其共生微生物产生的。本文对近些年来的海鞘天然产物的微生物来源的研究方法进行综述,包括可培养细菌的分离、不可培养细菌的粗提物检测、宏基因组学、全基因组测序等直接方法,以及化合物结构比对的间接方法。通过对海鞘-微生物共生体中天然产物生物合成来源的研究,不仅可以从根本上解决动物药源的问题,而且可为研究海鞘与微生物共生关系提供有力证据。     

Biomimetic syntheses of racemic natural products

Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought.     

Natural product inhibitors of ovarian neoplasia.

The present work constitutes a review of the literature on natural products with potential antitumor activity against ovarian neoplasias. The review refers to five plant extracts and sixty-nine compounds isolated from higher plants and microorganisms, which are classified in appropriate chemical groups and model tested, and cites their activity. Some aspects of recent research with natural products directed to ward producing drugs which are inhibitors of ovarian neoplasia are discussed.     

Natural products as catalysts for innovation: a pharmaceutical industry perspective

Natural products are evolutionarily designed and chemically distinct from most synthetic library molecules. In addition to their role as drugs, they are successfully used as molecular probes to identify disease relevant targets. Novel natural products are still routinely discovered from traditional sources through cultivation of microorganisms. Complementary approaches based on genome sequence information and subsequent annotation of biosynthetic pathways are emerging technologies. However, to be of practical use for drug discovery, these concepts must be advanced beyond their current state.     

红树林样品不经分离的微生物群体培养物生物活性研究

从海南、广西与广东三省的红树林区采集了181个样品,不进行微生物分离而直接作发酵剂接种到发酵培养基进行发酵,取发酵上清液进行抗细菌、抗真菌与肿瘤细胞毒活性的测定。同时对样品进行可培养微生物的分离与生物活性测定。结果显示:不同样品类型的生物活性差异较大。在15个具有强抗活性的样品中,有5个样品分离到的单株菌均无任何生物活性,说明这5个样品的生物活性可能是由微生物的群体作用产生的,也可能是某种没有培养出的微生物产生的。初步表明了探索微生物混合培养获得生物活性代谢产物的可能性。     

Production of natural value-added compounds: an insight into the eugenol biotransformation pathway

During the past few years, the production of natural value-added compounds from microbial sources has gained tremendous importance. Due to an increase in consumer demand for natural products, various food and pharmaceutical industries are continuously in search of novel metabolites obtained from microbial biotransformation. The exploitation of microbial biosynthetic pathways is both feasible and cost effective in the production of natural compounds. The environmentally compatible nature of these products is one major reason for their increasing demand. Novel approaches for natural product biogeneration will take advantage of the current studies on biotechnology, biochemical pathways and microbiology. The interest of the scientific community has shifted toward the use of microbial bioconversion for the production of valuable compounds from natural substrates. The present review focuses on eugenol biotransformation by microorganisms resulting in the formation of various value-added products such as ferulic acid, coniferyl alcohol, vanillin and vanillic acid.     

Marine drugs--macrolactins

The increasing demands for new lead compounds in pharmaceutical and agrochemical industries have driven scientists to search for new bioactive natural products. Marine microorganisms are rich sources of novel, bioactive secondary metabolites, and have attracted much attention of chemists, pharmacologists, and molecular biologists. This mini-review mainly focuses on macrolactins, a group of 24-membered lactone marine natural products, aiming at giving an overview on their sources, structures, biological activities, as well as their potential medical applications.     

Rare actinomycetes: a potential storehouse for novel antibiotics

New antimicrobial agents are desperately needed to combat the increasing number of antibiotic resistant strains of pathogenic microorganisms. Natural products remain the most propitious source of novel antibiotics. It is widely accepted that actinobacteria are prolific producers of natural bioactive compounds. We argue that the likelihood of discovering a new compound having a novel chemical structure can be increased with intensive efforts in isolating and screening rare genera of microorganisms. Screening rare actinomycetes and their previously under-represented genera from unexplored environments in natural product screening collections is one way of achieving this. Rare actinomycetes are usually regarded as the actinomycete strains whose isolation frequency is much lower than that of the streptomycete strains isolated by conventional methods. Many natural environments are still either unexplored or under-explored and thus, can be considered as a prolific resource for the isolation of less exploited microorganisms. More and different ecological niches need to be studied as sources of a greater diversity of novel microorganisms. In this review, we wish to update our understanding of the potential of the rare actinomycetes by focusing on the ways and means of enhancing their bio-discovery potential.     

极地微生物 —— 新天然药物的潜在来源

微生物是极地生态系统的重要组成部分.由于极地独特的地理、气候及环境特点,极地微生物所具有的新颖性与多样性,在科学研究、应用开发等方面都具有重要价值,并逐渐受到人们的广泛关注.有关极地微生物的资源勘探与代谢活性产物研究,已成为国际微生物学研究的热点之一.结合笔者的工作实践,对近年来极地微生物资源的勘探与收集情况进行了介绍,并着重对以医药与生物农药等为目标的极地微生物产活性化合物的研究现状进行了概述,同时还对目前一些影响研究工作开展的限制因素进行了讨论.可以预见,针对极地微生物资源的研究开发工作,将会给新型天然药物的筛选与发现带来新的机遇与突破.     

Marine Natural Products: The Important Resource of Biological Insecticide

Due to the unique environmental conditions and vast territory, marine habitat breeds more abundant biological resources than terrestrial environment. Massive marine biological species provide valuable resources for obtaining a large number of natural products with diverse structure and excellent activity. In recent years, new breakthroughs have been made in the application of marine natural products in drug development. In addition, the use of marine natural products to develop insecticides and other pesticide products has also been widely concerned. Targeting marine plants, animals, and microorganisms, we have collected information on marine natural products with insecticidal activity for nearly decade, including alkaloids, terpenes, flavonoids and phenols fatty acids, peptides, and proteins, et al. In addition, some active crude extracts are also included. This review describes the insecticidal activities of marine natural products and their broad applications for future research in agriculture and health.     

Bioactive Compounds from Marine Bacteria and Fungi

Marine bacteria and fungi are of considerable importance as new promising sources of a huge number of biologically active products. Some of these marine species live in a stressful habitat, under cold, lightless and high pressure conditions. Surprisingly, a large number of species with high diversity survive under such conditions and produce fascinating and structurally complex natural products. Up till now, only a small number of microorganisms have been investigated for bioactive metabolites, yet a huge number of active substances with some of them featuring unique structural skeletons have been isolated. This review covers new biologically active natural products published recently (2007–09) and highlights the chemical potential of marine microorganisms, with focus on bioactive products as well as on their mechanisms of action.     

Rare actinomycetes: a potential storehouse for novel antibiotics

New antimicrobial agents are desperately needed to combat the increasing number of antibiotic resistant strains of pathogenic microorganisms. Natural products remain the most propitious source of novel antibiotics. It is widely accepted that actinobacteria are prolific producers of natural bioactive compounds. We argue that the likelihood of discovering a new compound having a novel chemical structure can be increased with intensive efforts in isolating and screening rare genera of microorganisms. Screening rare actinomycetes and their previously under-represented genera from unexplored environments in natural product screening collections is one way of achieving this. Rare actinomycetes are usually regarded as the actinomycete strains whose isolation frequency is much lower than that of the streptomycete strains isolated by conventional methods. Many natural environments are still either unexplored or under-explored and thus, can be considered as a prolific resource for the isolation of less exploited microorganisms. More and different ecological niches need to be studied as sources of a greater diversity of novel microorganisms. In this review, we wish to update our understanding of the potential of the rare actinomycetes by focusing on the ways and means of enhancing their bio-discovery potential.     

Systematics-guided bioprospecting for bioactive microbial natural products

Advances in the taxonomic characterization of microorganisms have accelerated the rate at which new producers of natural products can be understood in relation to known organisms. Yet for many reasons, chemical efforts to characterize new compounds from new microbes have not kept pace with taxonomic advances. That there exists an ever-widening gap between the biological versus chemical characterization of new microorganisms creates tremendous opportunity for the discovery of novel natural products through the calculated selection and study of organisms from unique, untapped, ecological niches. A systematics-guided bioprospecting, including the construction of high quality libraries of marine microbes and their crude extracts, investigation of bioactive compounds, and increasing the active compounds by precision engineering, has become an efficient approach to drive drug leads discovery. This review outlines the recent advances in these issues and shares our experiences on anti-infectious drug discovery and improvement of avermectins production as well.     

Drugs from the seas - current status and microbiological implications

The oceans are the source of a large group of structurally unique natural products that are mainly accumulated in invertebrates such as sponges, tunicates, bryozoans, and molluscs. Several of these compounds (especially the tunicate metabolite ET-743) show pronounced pharmacological activities and are interesting candidates for new drugs primarily in the area of cancer treatment. Other compounds are currently being developed as an analgesic (ziconotide from the mollusc Conus magus) or to treat inflammation. Numerous natural products from marine invertebrates show striking structural similarities to known metabolites of microbial origin, suggesting that microorganisms (bacteria, microalgae) are at least involved in their biosynthesis or are in fact the true sources of these respective metabolites. This assumption is corroborated by several studies on natural products from sponges that proved these compounds to be localized in symbiotic bacteria or cyanobacteria. Recently, molecular methods have successfully been applied to study the microbial diversity in marine sponges and to gain evidence for an involvement of bacteria in the biosynthesis of the bryostatins in the bryozoan Bugula neritina.     

低温微生物及其酶类的研究概况

广泛分布在地球寒冷生境 ,如南北两极、高山、深海以及冰川中的低温微生物 ,不但为研究低温生态系统、生命起源与进化以及生物适冷机制提供了丰富的材料 ,同时在生物工程方面也具有潜在的巨大开发价值。国内外越来越多的科研人员对低温微生物及其产物的研究表现出了浓厚的兴趣。关于细胞膜和低温酶的研究 ,是目前微生物适冷机制研究中的 2个热点。就低温微生物的研究现状和适冷机制以及低温酶类的研究进行了综述。     

Basidiomycetes: A new source of secondary metabolites.

The area of natural products research is the most rapidly growing field of organic chemistry, due to the great technical developments in the isolation and identification techniques. Today, near to one million natural products -isolated from the most diverse living things- are known. Microorganisms are among the least-studied of these. Nevertheless, they offer large possibilities for the discovery of new structures and biological activities. Among the microorganisms, the Basidiomycetes present a production capacity and a range of biologically active metabolites, which have scarcely been investigated. The wide spectrum of natural products with biological activity produced by Basidiomycetes includes antimicrobial agents, antifungal, antiviral and cytotoxic activities, enzymes, plant growth regulators and flavors. These metabolites are generally grouped by their chemical origin, and the relationship between chemical structure and the different biological activities reported. The main objective of this review is to bring an updated revision of the numerous and interesting biosynthetic pathways from basidiomycetes.     

戊二酰亚胺类天然产物生物合成研究进展

微生物天然产物是天然药物的重要组成部分,而天然产物的良好生物活性很大程度上取决于发挥药效的结构基团。这些特殊药效基团的生物合成,通常是利用小分子羧酸、氨基酸等结构简单的初级代谢产物,经过复杂的生物化学过程,最终合成结构复杂活性多样的天然产物。戊二酰亚胺类天然产物是一类重要的细菌来源天然产物,它们具有良好的生物活性,是潜在的先导化合物,部分化合物已被开发成分子探针。本文综述了近年来微生物来源的戊二酰亚胺类天然产物及其生物合成研究,包括Iso-Migrastatin、Lactimidomyin、Cycloheximide、Streptimidone、Gladiostatin、Sesbanimide等,对戊二酰亚胺类天然产物的生物合成研究,将有效促进通过基因组挖掘策略寻找新型戊二酰亚胺类天然产物。