Bacaucin-1特异性抑制MRSA的构效关系研究

The rapid emergence and dissemination of multi-drug resistant bacteria worldwide is one of the greatest threats to public health and animal health as well. There is an urgent and unmet demand for new antibiotics. We found a new nonribosomal peptide, namely bacaucin in our previous work and its derivative bacaucin-1 could specifically kill methicillin-resistant Staphylococcus aureus (MRSA). However, the mode of action of bacaucin-1 on MRSA remains unclear. In the current proposal, we will first optimize the composition, charity and electronic states of each amino acid residues in bacaucin-1, to obtain neutrally or negatively charged bacaucin-1 derivatives with increased efficiency and safety, based on quantitative structure-activity relationship (QSAR) analysis. Additionally, the potential resistant gene of bacaucin-1 in the mutants will be identified and characterized through whole genome sequencing and transcript analysis. These results will provide insights to elucidate the mode of action of bacacucin-1, and shed light on the development of new antibiotics.

近年来，多重耐药菌的不断出现对人类健康和养殖业发展造成了巨大威胁，新型抗生素的开发迫在眉睫。在前期研究中，申请人报道了一种新型的非核糖体肽（bacaucin）及其衍生物bacaucin-1对MRSA具有特异性的杀菌作用，但机制尚不清楚。本项目将采用定量构效关系法优化bacaucin-1的氨基酸组成、手性及电荷特征，筛选出特异性高、抗菌活性强、中性或负电荷的短链bacaucin-1衍生物，旨在提高其稳定性和安全性。通过全基因组和转录组分析确定突变株对bacaucin-1耐药的靶基因，阐明bacaucin-1特异性抑制MRSA的分子机制。该研究将有助于发现新的药物靶点，为开发新型抗生素提供思路。

多重耐药细菌的不断出现对养殖业的发展以及人类健康造成了巨大的威胁，亟需开发新型抗菌药物或新的抗菌策略来应对耐药菌。在前期研究中，申请人报道了一种新型非核糖体多肽Bacaucin及其衍生物对MRSA具有特异性的杀菌作用，但其具体抗菌机制及构效关系还不清楚。为探究bacaucin衍生物的作用机制及其的普遍性，同时进一步扩大bacaucin类环状脂肽类药源分子的来源，我们首先基于前期发现的非核糖体多肽bacaucin-1，优化构效关系，设计并合成了系列衍生物，获得一种新型的线性非阳离子多肽bacaucin-1a，丰富药源分子库。为探究bacaucin膜靶向的作用机制，我们以黄酮类抗菌化合物为探针，发现其能有效靶向细菌的细胞质膜成分磷脂酰甘油（PG）和心磷脂（CL）导致细菌膜电势消散从而杀菌，为bacaucin衍生物的合理设计提供新思路。最后，结合抗菌药物的体内递送方式以及胞内MRSA感染特点，建立了按需给药的精准抗菌给药方案，为寡肽类抗菌化合物的体内高效递送提供技术支持。

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