Dept Research Areas
Streptomycetes produce the majority of antibiotics used in human and veterinary medicine and agriculture, as well as anti-tumour and anti-parasitic agents, herbicides, and other pharmacologically active metabolites (e.g. immuno-suppressants). In addition they make 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 both space and time. The Streptomyces research group at JIC is seeking knowledge of the genetics, molecular biology and physiology of streptomycetes and their relatives that will enable exploitation of these organisms for the benefit of society, as well as yielding a wealth of fundamental understanding with wide implications for bacterial genetics as a whole.
Much of our effort is focussed on the model organism, Streptomyces coelicolor A3(2). This organism is genetically the most studied member of the genus world-wide and has become the paradigm for the actinomycetes. More recently, we have also initiated studies on Streptomyces venezuelae, in large part because of its ability to sporulate in submerged liquid culture, thus facilitating biochemical studies of differentiation, and to provide a direct comparison with our work on S. coelicolor. We are studying the genetics of these two organisms at many levels with the aims of understanding Streptomyces as complex, differentiating bacteria as well as providing fundamental insights into the production of antibiotics and other valuable products.
Genetics, genomics and functional genomics
In a collaboration with the Sanger Institute at Hinxton, Cambridge and funded by the BBSRC and the Beowulf Genomics initiative of the Wellcome Trust, we sequenced the 8.7-Mb genome of S. coelicolor. The sequences of the 356-kb linear plasmid SCP1 and of the 31-kb circular plasmid SCP2* have also been determined, completing the sequencing of the entire genetic content of S. coelicolor (just over 9 Mb). We also have access to the entire genome sequence of S. venezuelae. Further details can be obtained from the S. coelicolor genome web site. A genomics database has been established at JIC by Dr. Govind Chandra (firstname.lastname@example.org) . Our extensive involvement in the acquisition and organisation of Streptomyces genome data has led to a growing interest in comparative genomics, both of different streptomycetes and of their actinomycete relatives, which include many bacteria of medical, industrial and environmental importance.
These sequence resources are underpinning our major efforts in functional genomics, including both micro-array and proteome analysis (we have identified nearly 1000 S. coelicolor-derived protein spots on 2-D gels and (with colleagues at the University of Manchester) have established a web site with example gels (http://dbkgroup.org/s_coeli/referencegel/). We have also developed a highly efficient PCR-based targeted gene disruption procedure that has been widely disseminated. In addition we have constructed 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.
Secondary metabolism and antibiotic production
We are studying the global and pathway-specific regulation of three clusters of antibiotic biosynthetic genes - for actinorhodin, methylenomycin and undecylprodigiosin - in S. coelicolor and the mechanisms of their differential expression in response to metabolic and developmental triggers. Following from genome sequencing, newly discovered gene clusters for unknown secondary metabolites are being studied in both S. coelicolor and S. venezuelae. We are analysing the mechanisms and programming of antibiotic biosynthesis, with particular emphasis on an unusual class of ribosomally synthesised antibiotics known as lantibiotics made by a number of different actinomycete strains. We are also investigating and engineering the metabolic and biochemical connections between primary metabolism, especially carbon metabolism, and secondary metabolism.
We are studying the functions, interactions and spatial and temporal expression of genes controlling aerial mycelium formation and the metamorphosis of aerial hyphae into spore chains; the modifications of cell division processes that lead into sporulation; and the significance of the synthesis of sporulation-associated proteins and pigments at specific times and cellular locations. These studies also reveal interconnections between morphological development and the production of secondary metabolites.
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.