Streptomycetes are used to produce the majority of antibiotics applied in human and veterinary medicine and agriculture, as well as anti-parasitic agents, herbicides, pharmacologically active metabolites (e.g. immuno-suppressants) and several enzymes important in the food and other industries. They are also unique amongst bacteria in their mycelial, sporulating life cycle, which involves complex regulation of gene expression in space and time. The Streptomyces research group is seeking knowledge of Streptomyces genetics, molecular biology and physiology, which will provide background to their use for applied objectives as well as yielding a wealth of fundamental knowledge of prokaryotic genetics with wide implications.

Underpinning this work is a continuing investigation of the basic genetics of streptomycetes and their accessory genetic elements, and the development of techniques of genetic analysis and manipulation. The focal point is the model organism, Streptomyces coelicolor A3(2).  S. coelicolor A3(2) is genetically the most studied member of the genus world-wide and is becoming the paradigm for the actinomycetes. We are studying its genetics at many levels. All the studies below are central to the understanding of Streptomyces as a complex, differentiating prokaryotic genetic system as well as to the production of antibiotics and other valuable products.

Genetics, genomics and functional genomics: In a collaboration with the Sanger Centre at Hinxton, Cambridge and funded by the BBSRC and the Beowulf Genomics initiative of the Wellcome Trust, we have sequenced the 8.7 Mb genome of S. coelicolor (Bentley et al. Nature 417: 141-147).  The sequence of the 356 kb linear plasmid SCP1 has also been completed.  Together with the sequence of the circular plasmid SCP2 (Hang et al., Microbiology, in press) this completes the sequencing of the entire genetic content of S. coelicolor (just over 9 Mb). Further details can be obtained from the S. coelicolor genome web site.  A new genomics database using a similar structure to the well-known Subtilist and Tuberculist has been established at JIC by Dr. Govind Chandra.

These resources are underpinning our major efforts in functional genomics, much of which is being carried out within a consortium of UK laboratories co-ordinated from JIC under the Investigating Gene Function Initiative (BBSRC).   At JIC one aspect of this involves proteomics: we have identified nearly 1000 protein spots on 2-D gels and (with colleagues at UMIST) have established a web site with example gels ( http://dbkweb.ch.umist.ac.uk/StreptoBASE/s_coeli/referencegel/). We have also developed a highly efficient PCR-based targeted gene disruption procedure and diseminated it by two recent practical courses.   In addition we have for the first time been able to constuct a comprehensive library of transposon-induced mutants. All of these resources are now being widely used. another aspect of our "community service" is our laboratory manual "Practical Streptomyces Genetics" compiled by research teams at the John Innes Centre and published in 2000.

New funding under the BBSRC'a Exploiting Genomics Initiative will allow us to undertake large scale mutagenesis and consequent phenotypic analysis.  Targeted topics within this will include the Tat export system, the aerobic/anaerobic interface; morphological differentiation; and (with Dr. Greg Challis, Warwick University) the study of genes for secondary metabolism.

Antibiotic biosynthesis: we are studying the organization and pathway-specific regulation of three clusters of biosynthetic genes - for actinorhodin, methylenomycin and undecylprodigiosin - and the mechanisms of their differential expression in response to metabolic and developmental triggers, including a novel mechanism of translational control via a transfer RNA for a rare codon: the role of ppGpp; and the ways in which extracellular g-butyrolactone signalling molecules bring about their effects. Following from genome sequencing , newly discovered gene clusters for unknown secondary metabolites are being studied. We are analysing the mechanisms and programming of antibiotic biosynthesis. We are also investigating and engineering the metabolic and biochemical connections between primary metabolism, especially carbon metabolism, and secondary metabolism.

Morphological differentiation: we are studying the functions, interactions and spatial and temporal expression of regulatory genes controlling aerial mycelium formation and the metamorphosis of aerial hyphae into spore chains; the modifications of cell division processes that lead into sporulation; the possible role of programmed glycogen and trehalose synthesis and degradation in morphogenetically significant turgor changes during aerial mycelium growth and sporulation; and the significance of the synthesis of sporulation-associated proteins and pigments at specific times and cellular locations.

Stress responses: Many of the unexpectedly large number (>65) of RNA polymerase sigma factors in S. coelicolor are likely to be involved in responses to environmental changes. We have made recent progress particularly in analysing responses to redox stress and cell wall defects. We have initiated studies of growth in anaerobic conditions.

Other actinomycetes: In collaboration, we are also applying our expertise in Streptomyces genetics and developmental biology to the improvement of Mycobacterium genetics and the understanding of its resting stage physiology, with applications for the understanding and possible control of diseases such as tuberculosis and leprosy.

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