报 告 人：Eung-Soo Kim, Professor
Department of Biological Engineering,
Inha University, Incheon, 402-751, Korea
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
报告时间：2月22日上午10：45
报告地点：生物药学楼800号报告厅
组织单位：分子微生物代谢实验室

Abstract The bacterial genus Streptomyces has long been appreciated for its ability to produce various kinds of medically important secondary metabolites, such as antibiotics, anti-tumour agents, immunosuppressants and enzyme inhibitors. Here, I present three examples of ‘Streptomyces Genomics-driven Novel & Improved Drug-lead Development’ approaches.1) The polyene antibiotics comprise a family of very valuable antifungal polyketide compounds, and are typically produced by soil actinomycetes. Using a polyene cytochrome P450 hydroxylase-specific genome screening strategy, Pseudonocardia autotrophica KCTC9441 was determined to contain an approximately 125.7 kb contiguous DNA region in five overlapping cosmids isolated from the P. autotrophica KCTC9441 genomic library revealed a total of 23 open reading frames, which are presumably involved in the biosynthesis of a nystatin-like compound tentatively named NPP. The deduced roles for six multi-modular polyketide synthase (PKS) catalytic domains were found to be highly homologous to those of previously identified nystatin biosynthetic genes. Disruption of a NPP PKS gene completely abolished both NPP biosynthesis and antifungal activity against Candida albicans, suggesting that polyene-specific genome screening may constitute an efficient method for isolation of potentially valuable previously-identified polyene genes and compounds from various rare actinomycetes widespread in nature. 2) Tautomycetin (TMC) is a novel activated T cell-specific immunosuppressive and anti-cancer compound. We cloned, sequenced, and characterized the entire biosynthetic gene cluster for TMC from Streptomyces sp. CK4412. Sequence information analysis of an approximately 110kb DNA region revealed two multi-modular type I polyketide synthases, type II Thioesterase, various proteins for dialkylmaleic anhydride biosynthesis, regulatory proteins and several tailoring enzymes. Moreover, we provide examples of generating potentially-valuable novel TMC analogs by targeted gene disruption.3) Streptomyces interspecies DNA microarray analysis was successfully used to detect global changes in mRNA abundance associated with doxorubicin overproduction in S. peceutius previously, revealing wblA A tetR-family transcriptional regulatory gene (SCO1712) disruption in S. coelicolor not only up-regulated antibiotic biosynthesis through pathway-specific regulators when a previously-identified pleiotropic down-regulatory wblA was expressed but also further stimulated antibiotic production in wblA-deletion mutant, implying that the SCO1712 might encode a novel antibiotic down-regulator. (SCO3579) and SCO1712 as pleiotropic down-regulators of antibiotic biosynthesis in Streptomyces species.