报告1题目：New Antibiotics from Microbial Genetic and Genomic Research
报 告 人：Lutz Heide, Professor
University of Tübingen, 72076 Tübingen, Germany
Abstract The aminocoumarin antibiotics novobiocin, clorobiocin and coumermycin A1 are produced by differentStreptomyces strains. They are potent inhibitors of bacterial gyrase and topoisomerase IV, and novobiocin has beenlicensed as antibiotic for clinical use (Albamycin?). They also have potential applications in oncology.
The biosynthetic gene clusters of all three antibiotics have been cloned and sequenced, and the function of nearly all genescontained therein has been elucidated. Rapid and versatile methods have been developed for the heterologous expressionof these biosynthetic gene clusters, and in Streptomyces coelicolor M512 as heterologous host these antibiotics wereproduced in yields comparable to those in the natural producer strains.
λ RED-mediated homologous recombination was used for genetic modification of the gene clusters in Escherichia coli.The phage ФC31 attachment site and integrase functions were introduced into the cosmid backbones and employed forstable integration of the clusters into the genome of the heterologous hosts. Modification of the clusters by single ormultiple gene replacements or gene deletions resulted in the formation of numerous new aminocoumarin derivatives,providing an efficient tool for the rational generation of antibiotics with modified structure.
Additionally, many new antibiotics were generated by mutasynthesis experiments, i.e. the targeted deletion of genesrequired for the biosynthesis of a certain structural moiety of the antibiotic, and the replacement of this moiety bystructural analogs which were added to the culture broth. The diversity of new structures obtained by this approach couldbe expanded by further genetic modifications of the gene deletion mutants, especially by expression of heterologous biosynthetic enzymes with appropriate substrate specificity.