耐甲氧西林金黄色葡萄球菌（MRSA）是临床感染的首要致病菌，具有高感染率、高致死率等特点，并且感染率逐年持续升高。开发针对MRSA感染的新型抗菌剂已成为本领域所急需。申请人前期研究发现，一株来源于红树根际土壤的真菌Penicillium janthinellum HK1-6可产生具有抗MRSA活性的azaphilone类化合物penicilones A-D。本项目拟采用化学表观遗传修饰策略对该真菌进行代谢调控，挖掘其合成azaphilone类化合物的代谢潜能，从中发现结构新颖的azaphilone类化合物；并在主产物penicilones A-B结构修饰的研究基础上，评价azaphilone类化合物及衍生物的抗MRSA 活性，分析其构效关系，确定高活性化合物的结构特征。本项目对azaphilone类化合物的挖掘及其抗菌构效关系的研究，可为开发针对MRSA感染的新型抗菌剂提供化合物基础。

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of health care-associated infections resulting in extensive morbidity and mortality. Therefore, there is an urgent need to develop additional effective anti-MRSA agents. In our previous studies, a fungal strain of Penicillium janthinellum HK1-6, derived from the mangrove rhizosphere soil, was found to produce anti-MRSA azaphilones, penicilones A-D. In this project, this fungal strain is planned to be metabolically regulated by chemical epigenetic modification to　exploit its biosynthetic potentials for azaphilones, for the purpose of obtaining new azaphilones from the modified fungal cultures. Additionally, a series of derivatives from the main secondary metabolites, penicilones A and B, will be designed by chemical modification. The anti-MRSA activities of azaphilones and their derivatives will be evaluated. Then the preliminary structure-activity relationships (SAR) of these azaphilones to anti-MRSA activity could be summarized and the structural characteristics of highly active azaphilone should be determined accordingly. This project would be able to provide compounds foundation for developing for new antibacterial agents towards MRSA infection.