结核病依然是最为严重的传染性疾病，其所引起的死亡率已经超过了HIV，位居传染性疾病之首。且随着耐药菌株、泛耐药菌株的出现和快速传播及与HIV的并发感染，给本已严峻的结核病的防控形势带来了新的挑战，迫切需求新的抗结核药物。在前期的研究中，我们从一株深海放线菌 SCSIO ZH16分离得到一类对结核分枝杆菌具有抑制活性的怡莱霉素，通过基因工程改造获得了强效抗结核抗生素怡莱霉素E，其体外抗结核活性为9.8 nM。本项目以此为基础，开展三方面的研究内容：利用响应面分析的方法开展怡莱霉素菌株的发酵优化、规模化发酵和怡莱霉素E的制备；利用低浓度诱导突变或亚浓度诱导突变法和亲和色谱法对怡莱霉素E的作用靶点和机制进行研究；开展怡莱霉素E的体内药效学研究，评价其体内抗结核活性。研究工作为怡莱霉素E的系统临床前研究奠定基础。

Tuberculosis (TB) ranks as the top infectious killer in the world, with the number of TB deaths exceeding those from human immunodeficiency virus (HIV). Moreover, the prevention and control of TB have become more difficult because of the co-epidemic of TB/HIV as well as the emergence and rapid dissemination of multi-drug resistant (MDR-TB), extensively drug-resistant (XDR-TB), and totally drug-resistant (TDR-TB) strains. Hence, novel anti-tuberculosis agents with increased potency and efficacy are urgently needed. In the previous studies, a kind of compounds isolated from a deep sea originated Streptomyces atratus SCSIO ZH16 were showed anti-tuberculosis activities, which were named ilamycins. By genetic engineering modification of the strain S. atratus SCSIO ZH16, more potent anti-tuberculosis ilamycins E were generated and the anti-tuberculosis of these compounds to Mycobacterium tuberculosis H37Rv were 9.8 nM. Based on these results, this project mainly focus on three aspects: 1) the optimization of the ilamycins E produced mutant strains, the large scale fermentation of the mutant strain and the large scale preparation of the ilamycins E. 2) the anti-tuberculosis mechanisms study of ilamycin E by inducing self-resistant and affinity chromatography approaches to identify the possible functional targets. 3) the in vivo pharmacodynamics study of ilamycin E. We hope the clinical studies of ilamycins E will be promoted based on the aforementioned studies.