Emerging biopharmaceuticals from marine actinobacteria

Actinobacteria are quotidian microorganisms in the marine world, playing a crucial ecological role in the recycling of refractory biomaterials and producing novel secondary metabolites with pharmaceutical applications. Actinobacteria have been isolated from the huge area of marine organisms including sponges, tunicates, corals, mollusks, crabs, mangroves and seaweeds. Natural products investigation of the marine actinobacteria revealed that they can synthesize numerous natural products including alkaloids, polyketides, peptides, isoprenoids, phenazines, sterols, and others. These natural products have a potential to provide future drugs against crucial diseases like cancer, HIV, microbial and protozoal infections and severe inflammations. Therefore, marine actinobacteria portray as a pivotal resource for marine drugs. It is an upcoming field of research to probe a novel and pharmaceutically important secondary metabolites from marine actinobacteria. In this review, we attempt to summarize the present knowledge on the diversity, chemistry and mechanism of action of marine actinobacteria-derived secondary metabolites from 2007 to 2016.     

海洋来源的放线菌次级代谢产物及其生物活性

放线菌是迄今最重要和最大的药用微生物种群。海洋放线茵生存于苛刻特殊的海洋环境，使其具备了复杂独特的代谢途径，其次级代谢产物在结构类型以及在生物活性等方面都呈现出与陆生放线茵不同的特点和多样性。多年来，诸多结构新颖、生物活性显著的天然活性产物持续从海洋来源放线茵代谢产物中被发现，这些活性化合物为新药研究提供了丰富的先导化合物，有些已进入研发阶段。近年，海洋放线茵活性产物的研究仍然是海洋微生物产物研究中值得关注的一个热点。本文按化舍物结构类型简要介绍了海洋来源放线茵代谢产物及其生物活性的研究概况。     

Drugs from the deep: marine natural products as drug candidates

In recent years, marine natural product bioprospecting has yielded a considerable number of drug candidates. Most of these molecules are still in preclinical or early clinical development but some are already on the market, such as cytarabine, or are predicted to be approved soon, such as ET743 (Yondelis). Research into the ecology of marine natural products has shown that many of these compounds function as chemical weapons and have evolved into highly potent inhibitors of physiological processes in the prey, predators or competitors of the marine organisms that use them. Some of the natural products isolated from marine invertebrates have been shown to be, or are suspected to be, of microbial origin and this is now thought to be the case for the majority of such molecules. Marine microorganisms, whose immense genetic and biochemical diversity is only beginning to be appreciated, look likely to become a rich source of novel chemical entities for the discovery of more effective drugs.     

Pharmacologically prospective antibiotic agents and their sources: A marine microbial perspective

Marine microbes have been a storehouse of bioactive metabolites with tremendous potential as drug candidates. Marine microorganism derived secondary metabolites (chemical compounds/peptides) are considered to be a burning area of research since recent past. Many of such compounds have been proven to be anti-bacterial, anti-fungal, anti-algal, anti-HIV, anti-helminthic, anti-protozoan, anti-tumor and anti-allergic agents. Marine bacteria and fungi have been reported to be the producers of such compounds owing to their defense mechanisms and metabolic by products. Although the number of natural products isolated from these classes of marine microbial flora is large, a limited number of such compounds reach the clinical trial and even less number of them get approved as a drug. Here we discuss the recent studies on the isolation, characterization and the pharmacological significances of anti-bacterial, anti-fungal and anti-infective agents of marine microbial origin. Further, the clinical status of such compounds has also been discussed in comparison with those derived from their terrestrial counterparts.     

海洋药物研究进展与发展趋势

迄今,人们已从各类海洋生物中分离获得14 500余种具有各种结构类型的海洋天然产物,其中20种已进入临床研究.运用新的研究方法和技术,开拓新的资源领域,将是解决药源问题的可行途径.笔者概述海洋药物的研究进展,展望海洋药物研究发展趋势.     

Cytotoxic anticancer candidates from natural resources

Natural products have been regarded as important sources that could produce potential chemotherapeutic agents. Over 50% of anticancer drugs approved by United States Food and Drug Administration since 1960 were originated from the natural resources, especially from terrestrial plants. Based on cytotoxicity bioassay, over 400 compounds have been isolated from plants, marine organisms and microorganisms from the period of 1996 to 2000. Recently, interest of natural product research has slowly moved to marine organisms. As a result, almost 50% of reported cytotoxic compounds were isolated from marine organisms such as sponges and corals. Also, traditional cytotoxic compounds of acetogenins, alkaloids and terpene skeletons have been reported continuously. In this review, we will present the cytotoxic compounds obtained from natural sources from 1996 to 2000, and the structures and cytotoxic activity of natural compounds isolated from territorial, marine and microorganism resources.     

From older toxic natural products to current drugs and drug candidates

Currently, and ignoring marine-sourced fatty acids/esters, there are 8 approved drugs(US FDA and Australia) that can be traced back to marine natural products initially isolated from a variety of sources. Six are directed towards cancers of man, one is for pain relief and one is an anti-HIV agent. These have come from the approximately 25,000 compounds currently reported from marine sources from approximately 1965. However,there are a substantial number of "toxic" agents that are either in clinical trials(as the initial compound or a derivative) or are potential "warheads" to be used with specific monoclonal antibodies. The 8 approved agents will be noted with brief comments, but the majority of the available time will be devoted to discussing agents from a variety of marine sources, that are either candidates for warheads, and/or have proceeded to PhaseⅡand Ⅲ trials in man against various cancers. The influence of older compounds that can be modified chemically to provide "interesting leads" will be one of the fundamental areas noted.     

海洋放线菌次级代谢产物及其抗菌、抗病毒、抗肿瘤活性研究进展

放线菌是发现大量药用天然产物的资源宝库,在微生物新药研究中占据着十分重要的地位。海洋放线菌生活环境特殊造就了其不同于陆地微生物独特的代谢途径,具有产生多种生物活性物质的潜力,是天然药用活性先导化合物的重要来源。从不同海洋生境来源放线菌的次级代谢产物中寻找生物活性物质已成为近年来的研究热点。目前已经分离到许多结构新颖、活性显著的化合物,为新药的研究提供了丰富的物质基础。本文主要对近3年（2015～2017）不同海洋生境来源且具有明显抗菌、抗病毒、抗肿瘤生物活性的放线菌次级代谢产物进行综述。     

Marine biodiversity as a source of chemical diversity

Total global biodiversity is estimated at between 3 and 500 × 10⁶ species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 10⁶ species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 10¹⁰ to 1.5 × 10¹² primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley-Less, Inc.     

Novel marine-derived anti-cancer agents

There is an immense diversity of marine plants and animals from which an estimated 14,000 pharmacologically active compounds have been isolated. However, in terms of clinically useful anti-cancer agents, the oceans remain as a largely untapped resource. Indeed, there are currently only two compounds used in the clinic that are derived from marine sources. These are cytarabine, which is a deoxycitidine analogue and aplidine, which has both growth inhibitory and anti-angiogenic effects. This situation is likely to change rather dramatically in the near future, as attention has focused on the vast diversity of available agents from marine organisms. The increased pace of activity in this area has resulted in a several clinical trials of promising compounds with the probability that these will be followed by other drugs currently under preclinical development.     

开发微生物来源天然产物的新技术

微生物在药物的开发中具有十分重要的作用,主要表现在微生物的次级代谢产物具有结构多样性、活性广泛性和临床有效性,其中许多化合物或其衍生物已经成为临床治疗多种疾病的药物。开发微生物来源的天然产物包括寻找新资源和革新新技术。本文介绍微生物药物的优点和局限性,获得更多微生物资源的途径以及微生物药物研发中5种新技术的应用,并探讨了各自的局限性。     

Novel antitumor agents: marine sponge alkaloids, their synthetic analogs and derivatives

Present review describes research on novel natural antitumor agents isolated from marine sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A great problem, to use directly the reservoir of marine organisms for therapy is the very low availability and the isolation of only very small amounts of the biologically active substances from the natural materials. Thus, the synthetic chemistry is required to develop high yield synthetic methods, which are able to produce sufficient marine alkaloids for a broad biological screening. This review will present some of the aspects of the medicinal chemistry developed recently to introduce such modifications. The structures, origins, synthesis and biological activity of a selection of N-heterocyclic marine sponge alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: pyrroles, pyrazines, imidazole, and other structural families. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of marine sponge alkaloids as an important source of leads for drug discovery.     

Natural products from marine invertebrates and microbes as modulators of antitumor targets

Over the last twenty-five to thirty years, exploration of the marine fauna and microbial flora has progressed from a random search by natural product chemists who liked to dive and wished to combine their hobby with their profession, to fully integrated programs of systemic investigation of the chemical agents elaborated by marine organisms of all phyla (as presumably defensive agents against predators) for their potential as leads to human-use drug candidates where the putative mechanisms have been identified as modulation of, and/or interaction with, potential molecular targets, rather than just exhibiting general cytotoxicity. This review is not exhaustive but is meant to cover the highlights of such agents and is arranged on a (nominal) target basis rather than by organism or chemical class.     

The use of marine-derived bioactive compounds as potential hepatoprotective agents

The marine environment may be explored as a rich source for novel drugs. A number of marine-derived compounds have been isolated and identified, and their therapeutic effects and pharmacological profiles are characterized. In the present review, we highlight the recent studies using marine compounds as potential hepatoprotective agents for the treatment of liver fibrotic diseases and discuss the proposed mechanisms of their activities. In addition, we discuss the significance of similar studies in Oman, where the rich marine life provides a potential for the isolation of novel natural, bioactive products that display therapeutic effects on liver diseases.     

Natural products from cyanobacteria: Exploiting a new source for drug discovery

In the 1990s, the pharmaceutical industry shifted its focus to a combinatorial chemistry approach to fill drug-discovery pipelines; however, more recently there has been renewed interest in natural products as sources of lead compounds. Cyanobacteria are prolific producers of natural products displaying enormous chemical diversity, yet, until recently, exploitation of the genera was hampered by a number of issues related to their handling. With most of these problems now resolved, cyanobacteria have the potential to expand the variety of natural products obtained from microorganisms. The relative disregard in the past of cyanobacteria compared with other microbial sources of natural products, as well as the huge chemical diversity and biological activities of their products, recommend them as an attractive source of novel drugs for use in diverse therapeutic areas.     

Purification and characterization of a novel peptide with antifungal activity from Bothrops jararaca venom.

Different peptides have been isolated from a wide range of animal species. It is has become increasingly clear that due to the development of antibiotic-resistant microbes, antibacterial and antifungal peptides have attracted the attention in recent years, in order to find new therapeutic agents. In this work, a novel peptide with high inhibitory activity against fungi growth have been isolated from the venom of the Brazilian snake Bothrops jararaca. A Sephacryl S-100 gel filtration column was employed for further separation of proteins. The FV fraction with high antifungal activity was named Pep5Bj, pooled and submitted to reverse-phase chromatography in HPLC. The fraction containing the isolated peptide inhibited the growth of different phytopathogenic fungi (Fusarium oxysporum and Colletotrichum lindemuthianum) and yeast (Candida albicans and Saccharomyces cerevisiae). The peptide minimal inhibitory concentration is comparable to other known antifungal peptides, like insect defensins and cecropins, found in the last years in a large diversity of animals. We investigate F. oxysporum cells membrane permeabilization using SYTOX Green uptake, an organic compound that fluoresces upon interaction with nucleic acids after penetration in cell with compromised plasma membranes. When viewed under fluorescence optical microscopy, F. oxysporum cells exposed to Pep5Bj display strong SYTOX Green fluorescence in the cytosol, especially in the nuclei. The SYTOX Green data suggested that this effect is related to membrane permeabilization. The molecular masses of this peptide was obtained by MALDI-TOF spectrometry and corresponded to 1370Da.     

微生物源抗耐甲氧西林金黄色葡萄球菌天然产物的研究进展

耐甲氧西林金黄色葡萄球菌(MRSA)是目前临床上感染严重的耐药性细菌之一，给人类健康造成了巨大威胁。万古霉素为目前治疗MRSA感染的最后一道防线，但耐万古霉素金黄色葡萄球的出现使对治MRSA新型药物的开发迫在眉睫。微生物是巨大的天然化合物宝库，曾为现代抗生素工业提供了多数主力抗生素。新近研究表明，微生物源天然产物有着良好的对治MRSA的生物活性，有些已经被开发为临床治疗MRSA感染的一线药物。本文从MRSA耐药机理，新型MRSA治疗药物研究的意义，到目前常用治疗MRSA的药物，尤其针对来源于微生物拮抗MRSA的天然产物研究进行了综述，并对未来发展趋势进行了展望。     

American Society of Microbiology 101st General Meeting

The application of sophisticated molecular biology, genetics and genomics has made possible the advanced analyses of microbial genes, the topology of DNA and chromosomes, and insight into the regulation of gene expression during all stages of the life cycle of microbes, both in vitro and in vivo. The struggle to control contagious pathogens continues world wide amidst resistance emergence to many classes of antimicrobial agents. Many hospital, research and community labs are applying themselves to a more thorough understanding of the molecular basis of this resistance. New drugs which improve on predecessor agents were presented. The following classes of antimicrobial agents were represented: quinolones, cephems, macrolides and natural products. New target opportunities against both lethal (essential) gene targets and virulence targets were presented throughout the conference. In addition, increasing attention to the involvement of microbial life forms in immune function and dysfunction were described in numerous presentations.     

微生物源抗耐甲氧西林金黄色葡萄球菌天然产物的研究进展

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major drug-resistant bacterial pathogens which has posed a great threat to human being. Vancomycin is currently the best and the last-resort antibiotic used for the treatment of MRSA infections. The emergence of vancomycin-resistant Staphylococcus aureus has justified the great urgency of the exploration of novel drugs against MRSA. The microbial-derived antimicrobial metabolites had enabled the modern antibiotic-industries and saved millions of lives in the past century. Notably, a panel of promising metabolites were found recently in microbes which demonstrated decent anti-MRSA activity.Some of them have been developed as first-line drugs used in clinic. This review went over the mechanism of MRSA resistance, the importance of the exploration of new MRSA therapeutics, the commonly used therapeutic drugs, as well as the potential natural products of anti-MRSA derived from microorganisms which had been found. Lastly, a perspective was made to cover the trends of the development of anti-MRSA agents of the microbial     

Natural products with anti-HIV activity from marine organisms

In order to combat the human immunodeficiency virus (HIV), diverse strategies have been developed to research on compounds which can be developed as therapeutic agents. Screening of natural products derived from numerous species has afforded metabolites with significant antiviral activity against the HIV. The marine environment representing approximately half of the global biodiversity offers an enormous resource for novel compounds. Currently more than 150 natural products with promising levels of anti-HIV activity have been isolated following bioassay guided protocols from aqueous or organic extracts of marine organisms. Some of the most characteristic marinemetabolites that have exhibited significant anti-HIV activity on different biochemical assays designed for chemotherapeutic strategies are: Cyanovirin-N, a protein from a blue green alga; various sulfated polysaccharides extracted from seaweeds (i.e. Nothogenia fastigiata, Aghardhiella tenera); the peptides tachyplesin and polyphemusin, which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus; sponge metabolites such as avarol, avarone, ilimaquinone and several phloroglucinols; and a number of metabolites from marine fungi such as equisetin, phomasetin and integric acid. Considering that number of unique metabolites that have been isolated from a small extent of the ocean's biological and chemical diversity, the oceans represent a virtually untapped resource for the discovery of novel bioactive compounds.