|1. Phosphorothioation of the DNA backbone|
A novel, site-specific, DNA backbone phosphorothioation has been discovered, and determined that it exists in widespread bacteria of variable origin and diverse habitat. The discovery is based on that high G+C gram-positive bacterium Streptomyces lividans 1326 contains DNA that is degraded by oxidative cleavage during electrophoresis in Tris-acetate buffer. A dnd gene cluster can replace the non-bridging oxygen in the DNA sugar phosphate backbone with sulfur to form a phosphorothioate linkage in a sequence- and stereo-specific manner. This unprecedented DNA sulphur modification seemed to have opened up a fascinating new field of research with potential relevance to the understanding of DNA damaging and repair agents.
|2. Novel natural product biosynthetic pathways|
Microbial secondary metabolites with structural diversity, biological diversity and activity-producing strain diversity, plays an important role in the research on the agricultural and medical antibiotics and their development. We are taking extreme environmental microbes (eg, addicted to pressure, addicted to pressure) or symbiotic bacteria as the main source to target major diseases, screening, and carrying out the purification and identification of biologically active microbial secondary metabolites with novel structures.
In addtion, dozen of biosynthetic gene clusters of microbial secondary metabolites have been cloned and identified, to clarify the biosynthetic pathway, and to reveal the molecular mechanism of enzyme-catalyzed reaction. The recombinant DNA technology is used to rationally modify the biosynthetic pathway, regulate and re-assemble, and new metabolic pathways are rebuilt to improve product yield and create “non-natural” natural products with novel structures.
Validamycin A gene cluster
|3. Microbial functional genomics and bioinformatics|
Comparative analyses have revealed that some bacterial species possess extremely plastic genomes. The optional genomic repertoire, termed as the 'mobilome' (mobile genome), includes a myriad of short strain-specific sequences, plasmids, transposons, integrons, prophages and a growing list of genomic islands. Recently we have been investigating the unique genotypes in Streptomyces, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella enterica by using ‘dry’- and ‘wet’-science-based approaches, aiming at rapidly defining genomic biomarkers of evolutionary lineage, phenotype, pathotype, chemotype, environmental adaptation and/or antibiotic biosynthesis. More details about bioinformatics at MML are available at http://bioinfo-mml.sjtu.edu.cn/.
In silico ‘subtractive hybridization’ of Streptomyces lividansTK24 against its close relative S. coelicolor A3(2) by using mGenomeSubtractor
|4. Genetic regulation of secondary metabolism in Streptomycetes|
Streptomycetes are Gram+ soil bacteria which are notable for their production of numerous secondary metabolites including anti-tumor agents, immunosuppressants and over two-thirds of all natural antibiotics. Streptomycetes has a complex lifecycle involving mycelial growth and spore formation. Both of the morphological differentiation and the secondary metabolism occurred at late growth phase, triggered by physiological and environmental signals, coordinated by a complex gene expression regulatory network. Using the modelorganism Streptomyces coelicolor A3(2) and the validamycin industrial producer as examples, and combining molecular biology and functional genomics approaches we are striving to understand the genetic regulation of morphological development and secondary metabolism in Streptomycetes.
|5. Regulation research on microorganism and plant interation by chemical ecology|
Recent studies found that microbial metabolites not only can regulate their own growth and development (geosmin from Streptomyces, etc.), but higher plants in many different functions, like growth promoting, disease resistance and abiotic tolerance enhancing (2,3- butanediol form Bacillus subtilis), etc. The research of this field focuses on the complicated metabolites from actinomycetes to identify signal molecules and investigate their biological effect on higher plants, animals by meanings of chemical ecology and functional genomics. Research in this field will help understand the interaction between microorganism and their host plants, the origination and evolution of this kind of interaction, especially the endophytic actinomycetes. Relevant research will pave the way for the efficient mining for the microbes producing target bio-pesticides and human medicine.
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