抗MRSA和VRE活性Fasamycin化合物的挖掘和构效关系研究

耐药菌感染严重威胁着人类健康，寻找针对耐药菌的新型抗菌素是解决细菌耐药问题的迫切需要。研究证明Fasamycin类化合物对耐药菌MRSA和万古霉素耐药屎肠球菌VRE有良好活性，其作用靶点是脂肪酸合成酶II的酮脂酰-ACP合成酶II (FabF)，有成为新型抗菌素先导物的潜力。我们前期从链霉菌SC1169菌株获得了30个Fasamycin类新化合物，证明其对MRSA和VRE有强抑菌活性，并完成了菌株全基因组测序和Fasamycin生物合成基因簇的注释。本项目拟在此基础上，运用OSMAC策略激活Fasamycin生物合成后修饰沉默基因、后修饰基因改造、化学衍生化获得结构多样的Fasamycin新衍生物，测定其抗菌活性和FabF靶点选择性及对哺乳动物细胞的毒性，阐明构效关系，发现对MRSA和VRE活性更强、选择性作用于原核细胞的化合物，为新型抗菌素的研发提供先导物。

Infections of drug-resistant bacteria are a growing threat to human health. Discovery of the new antibiotics with a new mode of action is a great need for human being to battle against drug-resistant bacteria. Fasamycins, a recently characterized class of polyketides, have demonstrated the strong activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). They have been elucidated to target FabF of type II fatty acid biosynthesis (FAS II). These have featured them as a potential lead of new antibiotics. In our previous investigation, 30 new fasamycins were obtained from the cultures of Streptomyces morookaense SC1169. Their structures, including axial chirality (atropisomerism), were fully elucidated. In our antibacterial evaluation some new compounds exhibited potent activity against both MRSA and VRE. Besides, the whole genome sequencing of this strain was completed and the biosynthetic genome cluster for fasamycins was annotated. In this proposed project, the follows will be carried out: (1) extend structural diversity of fasamycins by activating some silent genes through OSMAC approach and modifying key genes associated with the post-modifications in fasamycin biosynthesis and chemical modification; (2) evaluate the obtained fasamycins for in vitro antibacterial activity against various bacteria, including MRSA and VRE, and the selectivity of the compounds on FabF to understand their antibacterial potencies and spectra and their target selectivity to FAS II; (3) test in vitro cytotoxicity of the obtained fasamycins against mammal cells to examine their selectivity between prokaryotic and eukaryotic cells; and finally, (4) analyze structure-activity relationships of fasamycins in the antibacterial activity. It is expected that this project can lead to discovery of lead compounds for novel antibacterial agents and provide the basis for the synthesis and structural optimization of the antibacterial fasamycins and analogues.