强啡肽来源的抗菌肽的设计及活性研究
发布时间：2018-08-26 17:10
【摘要】：近年来,因抗生素滥用所引起的细菌耐药性感染已经成为全球性问题,严重威胁着人类健康。抗菌肽因其良好的抗菌活性和不易使细菌产生耐受的特性,一直活跃在国际学术研究的热点领域,有望成为新型抗生素的候选药物,并极大改善细菌感染类疾病的治疗现状。神经肽(NPs)是一类广泛存在于神经细胞或组织的小分子肽类物质,具有信号运输、免疫调节及抗菌等多重生物学活性。强啡肽(DYN)是继脑啡肽(ENK)之后于1979年发现的又一类神经肽,它除了参与行为调节和镇痛外,还能够穿过神经或非神经细胞,具有同抗菌肽类似的结构与理化性质。因此,基于抗菌肽、神经肽结构的相似性和功能的交叉性,我们对神经肽系列的强啡肽进行改造并合成了BA系列抗菌肽类似物。在体外抗菌活性筛选及细胞毒性评价的过程中发现,与母肽DYN相比,绝大多数BA类似物不仅保留了其低毒的特性,而且体外抗菌活性也得到了大幅度的提升。同时,在以BA-100/BA-84、BA-48/BA-52、BA-61/BA-85、BA-37/BA-83、BA-39/BA-87及BA-34/BA-103等代表性类似物的研究中发现,疏水性作为重要的理化参数,不仅影响类似物的杀菌速率,而且适宜范围内的改变能够使类似物在铜绿假单胞菌(P.aeruginosa 27853)和金黄色葡萄球菌(S.aureus 25923)间表现出作用活性差异,通常即使细菌失去细胞壁也不能消除这种差异。最后,我们又根据BA类似物在P.aeruginosa 27853和S.aureus 25923间作用活性所表现出的偏好性,选择最具代表性的BA-100、BA-83及BA-103等类似物,研究了其作用机制及在生物膜感染防治中的应用,发现BA类似物主要通过膜裂解机制而有选择性地发挥其抑杀活性,同时具有低浓度抑制P.aeruginosa 27853或S.aureus 25923生物膜形成,以及高浓度破坏S.aureus25923已形成生物膜的作用。总之,DYN经设计改造后,对其类似物所进行的抗菌活性、机制以及应用研究,不仅扩充了抗菌肽种类,而且对降低细菌耐药机制的影响具有重要意义。
[Abstract]:In recent years, antibiotic-resistant infections caused by the abuse of antibiotics have become a global problem and a serious threat to human health. Antimicrobial peptides have been active in the hot field of international academic research because of their good antibacterial activity and resistance to bacteria. They are expected to be candidates for new antibiotics and greatly improve the current situation of treatment of bacterial infectious diseases. Neuropeptide (NPs) is a class of small molecular peptides widely found in nerve cells or tissues. It has many biological activities, such as signal transport, immunomodulation and antimicrobial activity. Dynorphin (DYN) is a kind of neuropeptide discovered in 1979 after enkephalin (ENK). In addition to participating in behavioral regulation and analgesia, dynorphin (DYN) can also pass through nerve or non-nerve cells. It has similar structure and physicochemical properties as antimicrobial peptide. Therefore, based on the similarity of antimicrobial peptide, neuropeptide structure and function, we modified the dynorphin of neuropeptide series and synthesized BA series antimicrobial peptide analogs. In the course of in vitro antimicrobial activity screening and cytotoxicity evaluation, it was found that most of the BA analogues not only retained their low toxicity properties, but also greatly improved their antibacterial activity compared with the mother peptide DYN. At the same time, in the study of representative analogs such as BA-100/BA-84,BA-48/BA-52,BA-61/BA-85,BA-37/BA-83,BA-39/BA-87 and BA-34/BA-103, it was found that hydrophobicity, as an important physical and chemical parameter, not only affected the bactericidal rate of analogue, Moreover, the variation of the suitable range could make the analogues show different activity between P.aeruginosa 27853 and S.aureus 25923, which could not be eliminated even if the bacteria lost the cell wall. Finally, according to the preference of BA analogues between P.aeruginosa 27853 and S.aureus 25923, we selected the most representative analogues, such as BA-100,BA-83 and BA-103, to study the mechanism of their action and their application in the prevention and treatment of biofilm infection. It was found that BA analogue selectively exerts its inhibitory and killing activity mainly through membrane cleavage mechanism. At the same time, it can inhibit the formation of P.aeruginosa 27853 or S.aureus 25923 biofilm at low concentration, and destroy the formation of S.aureus25923 biofilm at high concentration. In a word, the antibacterial activity, mechanism and application of DYN have not only expanded the variety of antimicrobial peptides, but also played an important role in reducing the mechanism of bacterial resistance.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91;R96
本文编号：2205592
[Abstract]:In recent years, antibiotic-resistant infections caused by the abuse of antibiotics have become a global problem and a serious threat to human health. Antimicrobial peptides have been active in the hot field of international academic research because of their good antibacterial activity and resistance to bacteria. They are expected to be candidates for new antibiotics and greatly improve the current situation of treatment of bacterial infectious diseases. Neuropeptide (NPs) is a class of small molecular peptides widely found in nerve cells or tissues. It has many biological activities, such as signal transport, immunomodulation and antimicrobial activity. Dynorphin (DYN) is a kind of neuropeptide discovered in 1979 after enkephalin (ENK). In addition to participating in behavioral regulation and analgesia, dynorphin (DYN) can also pass through nerve or non-nerve cells. It has similar structure and physicochemical properties as antimicrobial peptide. Therefore, based on the similarity of antimicrobial peptide, neuropeptide structure and function, we modified the dynorphin of neuropeptide series and synthesized BA series antimicrobial peptide analogs. In the course of in vitro antimicrobial activity screening and cytotoxicity evaluation, it was found that most of the BA analogues not only retained their low toxicity properties, but also greatly improved their antibacterial activity compared with the mother peptide DYN. At the same time, in the study of representative analogs such as BA-100/BA-84,BA-48/BA-52,BA-61/BA-85,BA-37/BA-83,BA-39/BA-87 and BA-34/BA-103, it was found that hydrophobicity, as an important physical and chemical parameter, not only affected the bactericidal rate of analogue, Moreover, the variation of the suitable range could make the analogues show different activity between P.aeruginosa 27853 and S.aureus 25923, which could not be eliminated even if the bacteria lost the cell wall. Finally, according to the preference of BA analogues between P.aeruginosa 27853 and S.aureus 25923, we selected the most representative analogues, such as BA-100,BA-83 and BA-103, to study the mechanism of their action and their application in the prevention and treatment of biofilm infection. It was found that BA analogue selectively exerts its inhibitory and killing activity mainly through membrane cleavage mechanism. At the same time, it can inhibit the formation of P.aeruginosa 27853 or S.aureus 25923 biofilm at low concentration, and destroy the formation of S.aureus25923 biofilm at high concentration. In a word, the antibacterial activity, mechanism and application of DYN have not only expanded the variety of antimicrobial peptides, but also played an important role in reducing the mechanism of bacterial resistance.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91;R96
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