強(qiáng)啡肽來源的抗菌肽的設(shè)計(jì)及活性研究
發(fā)布時(shí)間：2018-08-26 17:10
【摘要】：近年來,因抗生素濫用所引起的細(xì)菌耐藥性感染已經(jīng)成為全球性問題,嚴(yán)重威脅著人類健康�？咕囊蚱淞己玫目咕钚院筒灰资辜�(xì)菌產(chǎn)生耐受的特性,一直活躍在國(guó)際學(xué)術(shù)研究的熱點(diǎn)領(lǐng)域,有望成為新型抗生素的候選藥物,并極大改善細(xì)菌感染類疾病的治療現(xiàn)狀。神經(jīng)肽(NPs)是一類廣泛存在于神經(jīng)細(xì)胞或組織的小分子肽類物質(zhì),具有信號(hào)運(yùn)輸、免疫調(diào)節(jié)及抗菌等多重生物學(xué)活性。強(qiáng)啡肽(DYN)是繼腦啡肽(ENK)之后于1979年發(fā)現(xiàn)的又一類神經(jīng)肽,它除了參與行為調(diào)節(jié)和鎮(zhèn)痛外,還能夠穿過神經(jīng)或非神經(jīng)細(xì)胞,具有同抗菌肽類似的結(jié)構(gòu)與理化性質(zhì)。因此,基于抗菌肽、神經(jīng)肽結(jié)構(gòu)的相似性和功能的交叉性,我們對(duì)神經(jīng)肽系列的強(qiáng)啡肽進(jìn)行改造并合成了BA系列抗菌肽類似物。在體外抗菌活性篩選及細(xì)胞毒性評(píng)價(jià)的過程中發(fā)現(xiàn),與母肽DYN相比,絕大多數(shù)BA類似物不僅保留了其低毒的特性,而且體外抗菌活性也得到了大幅度的提升。同時(shí),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等代表性類似物的研究中發(fā)現(xiàn),疏水性作為重要的理化參數(shù),不僅影響類似物的殺菌速率,而且適宜范圍內(nèi)的改變能夠使類似物在銅綠假單胞菌(P.aeruginosa 27853)和金黃色葡萄球菌(S.aureus 25923)間表現(xiàn)出作用活性差異,通常即使細(xì)菌失去細(xì)胞壁也不能消除這種差異。最后,我們又根據(jù)BA類似物在P.aeruginosa 27853和S.aureus 25923間作用活性所表現(xiàn)出的偏好性,選擇最具代表性的BA-100、BA-83及BA-103等類似物,研究了其作用機(jī)制及在生物膜感染防治中的應(yīng)用,發(fā)現(xiàn)BA類似物主要通過膜裂解機(jī)制而有選擇性地發(fā)揮其抑殺活性,同時(shí)具有低濃度抑制P.aeruginosa 27853或S.aureus 25923生物膜形成,以及高濃度破壞S.aureus25923已形成生物膜的作用。總之,DYN經(jīng)設(shè)計(jì)改造后,對(duì)其類似物所進(jìn)行的抗菌活性、機(jī)制以及應(yīng)用研究,不僅擴(kuò)充了抗菌肽種類,而且對(duì)降低細(xì)菌耐藥機(jī)制的影響具有重要意義。
[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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R91;R96
本文編號(hào)：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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R91;R96
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