Abstract:2012年12月在上海召开的“首届中国放线菌生物学与产业化研讨会”标志着我国放线菌研究专业学术组织的正式成立。从建国初期开始, 经过几代放线菌研究者的不懈努力, 从无到有, 不断开拓、发展和创新放线菌的基础和应用研究, 使得我国放线菌研究的队伍不断壮大, 若干方向的研究水平处于国际前沿。为了展现放线菌研究的最新进展, 《微生物学通报》针对本次研讨会组织出版了本期“放线菌生物学与生物技术专刊”, 以期促进放线菌及相关研究领域的发展。

Abstract:Daptomycin, produced by Streptomyces roseosporus, is a novel cyclic lipopeptide antibiotic against Gram-positive pathogenic bacteria. It is regarded as a potent antibiotic following vancomycin, the last defense line of antibiotics. This review summarizes the research advances of daptomycin in recent years, mainly including structure, action mechanism, biosynthesis and genes involved in biosynthesis of daptomycin. The strategies of combinatorial biosynthesis are also reviewed to study the relationship between structure and the anti-microbial activity to find potent daptomycin derivatives with a wider spectrum and higher anti-microbial activities. Finally, some strategies to improve daptomycin yields are also introduced, which will be the basis to reduce the daptomycin cost in industrial production.

Abstract:Actinobacteria are known to produce various natural products, including many important antibacterial and antitumor antibiotics. Glycosylation is a common tailoring reaction in natural product biosynthesis. In most cases, glycosylation significantly affects the bioactivity of natural products. The glycosylation of natural products could be manipulated by in vivo genetic engineering or by in vitro enzymatic glycodiversification approaches. A large number of new glycosylated products were generated using these two approaches, and some of them showed enhanced bioactivity. These new glycosyl-diversified products offer new opportunities for drug development.

Abstract:Nonribosomal peptide synthetases (NRPSs) catalyze the formation of complex peptide natural products, of which many display therapeutically useful activity. Conventional NRPSs have been characterized as modular and co-linear assembling. Recent studies of many NRPS systems revealed some examples where the catalytic logic does not directly correspond to the linear arrangement of modules and domains. This mini review summarizes the recently discovered NRPS biosynthetic pathways focused on four types of unconventional assembling ways including iterative NRPSs, nonlinear NRPSs, module skipping NRPSs and the nonribo-somal propeptide biosynthetic mode.

Abstract:Amino acids, natural small molecules that are important materials for constituting living organisms, play important roles in natural products biosynthesis. Tryptophan has a unique indole ring structure which possesses more modification sites than other amino acids. In studies on microbial natural products biosynthesis, tryptophan and its derivatives often serve as structural moieties that are incorporated into the natural products structures. Here, we summarize different modification patterns of tryptophan, including alkylation, halogenation, hydroxylation, indole ring-open and rearrangement reactions. Analyzing and summarizing the enzymatic modifications of tryptophan could help us understand the structure diversities of natural products and lay the foundation for our study of the mechanism of the novel natural product biosynthesis.

Abstract:Actinobacteria are well known as they can produce a series of secondary metabolites with complex structures and various bioactivities. The industrial production of these secondary metabolites plays a vital role in medical and agricultural fields. Recent advances in strain improvement, bioprocess optimization and control, and fermentation scale-up were reviewed here. The holistic viewpoints and approaches applied in industrialized production of secondary metabolites by actinobacteria were discussed as well as the perspectives.

Abstract:Recently, with the development of isolating and detecting large plasmids and high-throughput DNA sequencing technology, rapid progresses have been made on Streptomyces large circular and linear plasmids. In contrast to bacterial theta-type plasmids, Streptomyces theta-type plasmids reveal diversity and novelty on the structures of replication origins, functions of replication and regulation proteins. The newly identified replication origins of linear plasmids show that it can also be located near one telomere, and two or more functional origins are observed in one molecule. The newly sequenced telomeres indicate that formation of secondary structure rather than “folding-back” is important for telomere replication. Sequences of Streptomyces circular and linear plasmids imply their close relationship. Sequencing results also show that co-integration of circular plasmid and phage, and experiments demonstrate their inter-conversion under certain conditions. These results indicate that diversity, novelty and evolutionary relationship of Streptomyces circular and linear plasmids and phages.

Abstract:Streptomyces and other actinobacteria are important sources for bioactive products. In the light of whole genome sequencing technology, people have gained further information about Streptomyces. There exists a plethora of secondary metabolic pathways in Streptomyces, which exceeds the number of natural products that have been isolated under normal laboratory conditions. The expression of secondary metabolic pathways is regulated by a precise and sophisticated regulatory network. TetR family in Streptomyces is of great value in the regulatory network due to its huge number and multifunction. TetR family members could sense the environment changes through binding to specific GBL (gamma butyrolactone) molecules or other ligands with the help of the ligand binding domain, and subsequently repress or activate secondary pathways through regulating the expression of downstream target genes. This review will focus on the classification of TetR family proteins in Streptomyces based on their function and ligands they bind, and list the regulatory mechanism of known TFRs (TetR family regulators) on secondary metabolism in Streptomyces.

Abstract:Streptomyces is characterized by its strong ability to produce an impressive array of secondary metabolites with important biological activities, such as antibiotics, anti-tumor drugs and immunosuppressors widely used clinically. In streptomycetes, the biosynthesis of secondary metabolites is under strict, multilevel regulation involving pathway-specific, pleiotropic as well as global regulators. Inactivation or overexpression of some important regulatory genes could greatly influence the production of secondary metabolites, implying that a better understanding how regulatory genes function in secondary metabolism will have great potential application values. Among them, two-component system (TCS) as the signal transduction system in bacteria has been the research focus in the past few years. Increasing evidences demonstrate that TCS plays a global regulatory role during secondary metabolic processes in Streptomyces. This review summarizes the research progress of TCS, including typical TCS, orphan histidine kinases (HKs) and response regulators (RRs), involved in the regulation of secondary metabolism in the model strain of Streptomyces, Streptomyces coelicolor. The functional identification and the mechanistic characterization of these TCS have provided a valuable theoretical basis for the directed genetic engineering to improve the yield of important secondary metabolites in industrial streptomycetes.

Abstract:Actinobacterial systematics is the theoretical basis for the research and development of actinobacterial resources, and has become an independent subject, which includes actinobacterial classification, identification and nomenclature. Academician Shun-Chu Yan and his colleagues initiated actinobacterial systematics research in China since the 1950’s. With the efforts by several generations for over 60 years, Chinese scientists have published many new taxa in the past 10 years in International Journal of Systematics and Evolutionary of Microbiology, one of the top level journals in this field. Some new taxonomic technology and also the newly updated classification system done by some Chinese scientists have been adopted and cited; all these reflect that Chinese research teams on actinobacterial systematics have become an indispensable reference in the world of microbial systematics. This review will comprehensively introduce the origins and early history of Chinese actinobacterial systematics, analyse its present status, and also give its future directions.

Abstract:The growing bacteria drug resistance has seriously threatened the “antibiotic miracle”, while traditional approaches for new antibiotics discovery could not combat this problem and novel solutions are urgently needed. Recently, new methods and technologies such as novel screening model establishment, genome mining and combinatorial biosynthesis have revolutionized the screening of natural products. Applying these technologies offers a unique opportunity to re-establish actinobecteria as a major source for drug discovery. These new advances and technologies are described in this review.

Abstract:Actinobacteria are a class of microorganisms that can produce plenty of bioactive small molecule drugs, making an outstanding contribution to the human health. During the past decades, microorganisms derived and eventually marketed drugs become fewer and fewer, in the meanwhile, the problem caused by drug resistance pathogens become more and more serious, so people look forward to the new drugs urgently. Synthetic biology, which is developing fast in the past 10 years, plays an important role in the research and development of secondary metabolites. The biosystem is designed and rebuilt under the guidance of engineering science, from which the indiscoverable secondary metabolites can be obtained through heterologous expression. What is more, the rational designed gene cluster and the utilization of bio-elements lead to the new compounds that do not exist in nature as well as yield improved strains. The new techniques and methods of DNA assembly are also introduced, which make convenience to the researchers on secondary metabolites.

Abstract:Genome mining of natural product biosynthesis employs genome sequences to predict the biosynthetic potential of the producer strains guiding the purification and structure elucidation of novel compounds, and has been successfully applied in natural product discovery in both bacterial and fungal systems. In this review, the latest advances of genome mining of marine actinobacteria have been summarized, with emphasis on bioinformatic tools for sequence analysis and prediction of chemical structures, strategies for isolation of targeted natural products under the guidance of genome sequence information, activation of silent gene clusters and heterologous expression, as well as transcriptome mining developed by domestic scholars. Genome mining based on imaging mass spectrometry (IMS) was addressed as well. Although genome mining of marine actinobacteria has not been fully explored, we believe that genome mining will greatly facilitate natural product research in the near future not only in culturable marine actinobacteria, but also in mining of metagenomes in yet unculturable actinobacteria. We also propose that genome mining is not restricted in the identification of new structural and regulatory genes, and it is also important to discover and utilize various other genetic elements, including promoters with different strengths and sequences that response to various environmental conditions and signals, as well as small regulator RNA molecules.

Abstract:With many Streptomyces genomic sequences made available by next generation sequencing (NGS), the bioinformatics resource comes as the answer to an acute demand of the big data mining. In this study, I collected the frequently used tools and open-access databases for genome alignment and island detection, suitable for the large Streptomyces genomes with high G+C content. To illustrate these user-friendly tools, I identified the Actinobacteria integrative and conjugative elements in 12 completely sequenced Streptomyces genomes, which were found to be inserted into the core regions of the Streptomyces chromosomes. The bioinformatics resources currently available for secondary metabolites isolated from Streptomyces species are also described briefly, such as the web-based tool ThioFinder to rapidly identify thiopeptide biosynthetic gene cluster from DNA sequence using a profile Hidden Markov Model approach.

Abstract:Biosynthetic pathway genes for each natural product are mostly located together on a large and continuous segment of the genome to compose a gene cluster. Actinobacteria genomes usually contain various natural product biosynthetic gene clusters, which are valuable resources of potential applications in medicine, agriculture and industry. Some of these gene clusters are considered to be silent because no related metabolites could be detected under laboratory conditions. For functional analyses of natural product biosynthetic gene clusters, researchers constructed a lot of high-capacity vectors and many heterologous hosts by genetic engineering for cloning and expressing large DNA fragments of actinobacteria genomes in the last two decades.

Abstract:Great strides of Mycobacterium multi-omics have been achieved by the global Mycobacterium consortium, which deepened the biology of mycobacterium and provided novel insights into the evolution, better diagnostic markers and drug targets. We extracted relevant data from publically available papers and database to define the progress of Mycobacterium omics over the last decade and envision further crucial directions.