紫色色杆菌no.968产生的FK228是FDA批准的用来治疗皮肤T细胞淋巴瘤的抗癌药物，是一种组蛋白脱乙酰基酶(HDAC)抑制剂(HDACi)，由非核糖体肽合酶(NRPS)和聚酮合酶(PKS)催化合成。本项目计划通过NRPS模块替换和差向异构酶结构失活改造负责FK228合成的NRPS基因来获得FK228的结构类似物。各种与FK228类似但含有不同L型（或D型）氨基酸残基（或氨基酸衍生物）的二环缩酚酸肽类化合物组成FK228结构类似物库，利用不同的HDAC对化合物库进行筛选，获得对HDAC抑制活性高于FK228的化合物，以及对HDAC抑制的选择性与FK228不同的化合物。用已构建的大肠杆菌异源表达系统合成这些潜在的药物，通过基因工程和发酵条件优化来提高其产量。利用研究工作的过程中收集到的NRPS模块搭建NRPS模块平台，为其他革兰氏阴性菌来源的非核糖体肽类药物的组合生物合成改造提供便利。

FK228, producted by Chromobacterium violaceum no. 968, is an FDA-approved anticancer agent for the treatment of cutaneous T-cell lymphoma as a histone deacetylase (HDAC) inhibitor(HDACi).FK228 is biosynthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthetases (PKSs). Here, we plan to engineer NRPS genes responsible for FK228 biosynthesis by means of NRPS module replacement and epimerase domain inactivation.The analog library includes all kinds of FK228-like bicyclic depsipeptides with different L- (or D-) amino acid residues (or amino-acid derivatives) and will be screened using different HDAC isoforms to identify new compounds with superior HDAC inhibitory activity than that of FK228, and compounds with different selectivity of HDAC inhibition. An established heterologous expression system in Escherichia coli is chosen to biosynthesize the selected compounds as drug candidates and compound production will be improved through genetic engineering and fermentation optimization.Buliding a module platform of NRPS modules collected througnt this project will facilitate future combinatorial biosynthesis of nonribosomal peptide drugs produced by G- bacteria.