靶向优化的新型抗菌肽MS-PT1a抗耐甲氧西林金黄色葡萄球菌的作用与机制研究

With the increasing number of bacterial resistance to conventional antibiotics, it is vital to search for novel substances against resistant bacteria with well-defined antimicrobial mechanisms that could be developed into new and effective antibacterial drugs. Antimicrobial peptides are considered promising treatment options to combat infections by resistant bacteria not effectively treatable with conventional antibiotics. The previous studies found that MS-PT1a, a modified form of the novel natural antimicrobial peptide, exhibited potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity but the underlying mechanism of antimicrobial action is still unclear. In addition, the result of FITC-labelled localization study revealed the accumulation of MS-PT1a on the cell membrane and inside the cells, indicating that the antibacterial effect was probably achieved via multiple ways. MS-PT1a downregulated the transcription of the mecA gene in MRSA and inhibited biofilm formation, suggesting that MS-PT1a may play an anti-MRSA and anti-biofilm role by affecting the upstream (p)ppGpp signal pathway. Based on previous studies, it is necessary to illustrate the antimicrobial mechanism of MS-PT1a, including the elucidation of specific target organs, exploration of the regulation of (p)ppGpp pathway and evaluation the therapeutic index of animal infection model. The antimicrobial action of MS-PT1a was elucidated respectively from the molecular, cell and overall animal levels, which might provide a new approach to combat the bacteria resistant to conventional antibiotics.

抗生素枯竭与细菌耐药性日益加剧，使寻找新型的作用机制明确的抗耐药菌前体药物有着重要的意义。申请者通过对天然抗菌肽的靶向构效优化得到衍生肽MS-PT1a，出现强效抗MRSA作用，但其作用机制尚不十分清楚。前期研究发现MS-PT1a既能够在MRSA细胞膜上聚集又可进入细胞内，提示其可能通过不止一种机制发挥抗菌作用。同时，MS-PT1a对耐药性mecA转录的抑制和对MRSA生物膜形成的抑制，提示其可能通过影响二者上游胞内共同(p)ppGpp信号通路发挥作用。本项目在明确靶向优化的新型抗菌肽MS-PT1a抗MRSA作用基础上，探究发挥抗菌效应的作用靶位，明确其对耐药控件与生物膜作用机制，并建立动物感染模型确认体内治疗效果。分别从分子、细胞和整体动物水平阐明MS-PT1a作用机制，为开发新型的抗耐药菌药物提供理论依据和实验基础。

抗生素枯竭与细菌耐药性日益加剧，使寻找新型的作用机制明确的抗耐药菌前体药物有着重要的意义。申请者通过对天然抗菌肽的靶向构效优化得到衍生肽MS-PT1a，出现强效抗MRSA作用，研究发现MS-PT1a能影响MRSA细胞膜电位从而影响细菌细胞膜通透性导致细菌死亡。转录组结果表明MS-PT1a能显著下调肽聚糖合成过程中相关基因，影响细菌耐药的PBP2a 蛋白的表达。本项目在明确靶向优化的新型抗菌肽MS-PT1a抗MRSA作用基础上，探究发挥抗菌效应的作用靶位，明确其对耐药控件作用机制，并建立动物感染模型确认体内治疗效果。分别从分子、细胞和整体动物水平阐明MS-PT1a作用机制，为开发新型的抗耐药菌药物提供理论依据和实验基础。由国家自然科学基金项目支持完成了，具有自组装趋势的新型抗菌肽DMS-PS2的鉴定、破膜机制、对细菌生物膜清除作用以及对耐甲氧西林金黄色葡萄球菌创面感染的治疗作用；红眼叶蛙皮肤分泌物中一种增肌十肽的鉴定；臭蛙皮肤分泌物中短缩素-1肽N端衍生物的抗菌活性增强研究等三项项目研究。