链霉菌GB-2中西索米星与新霉素共合成的代谢机制研究

Both sisomicin and neomycin are aminoglycosides derived from paromamine, which are produced normally by Micromonospora inyoensis and Streptomyces fradiae respectively. Significantly, a marine Streptomyces strain S. sp. GB-2 can yield both antibiotics at certain fermentation conditions. Genome scanning of S. sp. GB-2 found only one set of paromaine biosynthetic genes locating in the neomycin cluster, which suggested that sisomicin and neomycin share the paromamine biosynthetic genes in S. sp. GB-2. Researches on sisomicin biosynthesis have been impeded seriously since genetic manipulation of M. inyoensis is not amenable. We circumvent this difficulty by establishing the genetic system of S. sp. GB-2, another producer of sisomicin. The biosynthetic pathway of neomycin is almost clear. However, there is no report on the regulatory mechanism of neomycin production. In this project, we will use the special marine Streptomyces sp. GB-2 as a model organism to delineate the biosynthetic pathway of sisomicin, to elucidate the neomycin regulatory mechanism and to depict the relationship between sisomcin and neomycin production in S. sp. GB-2. Both sisomicin and neomycin are widely used anti-infection drugs. Our studies will demonstrate the detailed metabolic mechanisms of sisomicin and neomycin and set the stage for a better utilization of the two antibiotics.

西索米星和新霉素都是以巴龙霉胺为前体合成的氨基糖苷类抗生素，一般由尤尼小单孢菌和弗氏链霉菌分别产生。我们发现海洋链霉菌GB-2在特定发酵条件下可以同时产生这两种抗生素。对链霉菌GB-2基因组的扫描测序发现唯一的一组巴龙霉胺合成基因存在于新霉素的基因簇中，说明在链霉菌GB-2中西索米星和新霉素共用了巴龙霉胺的合成基因。西索米星的生物合成研究受困于产生菌尤尼小单孢菌的遗传操作困难，开展得并不深入。我们已经建立起链霉菌GB-2的遗传操作系统，避开了这个难题。另外，对新霉素代谢调控机制的研究至今未见报道。鉴于此，我们将利用这株特殊的链霉菌GB-2为研究材料，力求阐明西索米星的生物合成途径，揭示新霉素的代谢调控机制，并探索链霉菌GB-2中这两种抗生素代谢之间的关系。西索米星和新霉素都是临床应用广泛的抗感染药物。我们的研究将深入地揭示它们的代谢机理，为更好地利用这两种重要的抗生素打下基础。