基因组学指导下深海真菌Penicillium sp. SCSIO sof101抗革兰氏阴性菌活性次级代谢产物的挖掘

革兰氏阴性（G-）耐药菌临床检出比例高达70%，但相对滞后的药物研发速度，使其逐渐危及全球。过去受资源、方法等因素的限制，抗G-细菌药物先导化合物的研发速度成为制约新型药物研发的瓶颈。海洋真菌的大量沉默NRPS及其杂合基因簇，具有生产抗G-细菌活性先导化合物的潜力。后基因组时代的到来，为挖掘这些活性化合物提供了契机。本项目拟在前期研究基础上，以深海真菌Penicillium sp. SCSIO sof101等为研究对象，以抗G-细菌活性先导化合物为目标，对沉默NRPS及其杂合基因簇，通过传统OSMAC策略与转录调控、异源表达等基因挖掘手段相结合，激活菌株潜能，挖掘抗G-细菌活性的次级代谢产物，为抗G-细菌药物的研发提供先导化合物。该项目将为抗G-细菌先导化合物的发现提供借鉴，为早日实现具有我国自主知识产权的抗G-细菌药物奠定基础。

Multidrug resistant Gram-negative (G-) bacterial pathogens register a detection rate as high as 70% in hospital environments, posing a serious threat to global healthcare systems due to a dwindling pipeline of anti-infective drugs. A dearth of sustainable bioresources and technologies present a bottleneck in the discovery of the lead compounds in the past. However, abundant silent biosynthesis gene clusters are present in fungi, especially silent nonribosomal peptide synthetase (NRPS) and its hetero gene clusters, which can potentially be exploited to produce lead products targeting G- pathogens. The advent of the post-genomics era opens up opportunities of exploring such active compounds. The application is based on our previous research, which will continue to mine novel compounds with against G- bacteria activities from the deep-sea fungus Penicillium sp. SCSIO sof101. It will focus on the NRPS and its hetero gene clusters to identify their promising bioactive compounds. Firstly, the strategies of traditional OSMAC methods, transcriptional regulation, heterologous expression, and so on, will be integrated and extensively used to active the potent silent NRPS and its hetero gene clusters. Secondly, the silent gene cluster which is activated will be large scaled fermentation. The produced compounds will be isolated and structure elucidated. Thirdly, the mined compounds will be screened for their bioactivities including against G- bacteria and other pathogens. These will explore the way to offer novel lead compounds and lay a foundation for the discovery of new anti-infective drugs against G- bacteria with our own intellectual property rights.