抗菌肽的来源、作用机制及临床应用研究进展
Sources, Mechanism and Clinical Application of Antimicrobial Peptides

作者: 吴阳开 , 金明昌 :广东容大生物股份有限公司,广东 清远;

关键词: 抗菌肽抗生素耐药性治疗药物临床试验免疫调节活性Antimicrobial Peptides Antibiotic Resistance Therapeutic Drugs Clinical Trials Immunomodulatory Activity

摘要:
抗菌肽(Antimicrobial peptide, AMPs)又叫宿主防御肽(Host defence peptide, HDPs),通常是由7~100个氨基酸组成的小分子多肽,是生物体天然免疫防御系统的一个重要组成部分。AMPs具有广谱抗感染性细菌(G+、G)、抗病毒、抗真菌、抗寄生虫、抑杀肿瘤细胞和免疫调节等生物学活性。AMPs通过膜作用和非膜作用两种机制抑杀病原菌。AMPs由于其潜在的治疗作用,近年来受到了人们的广泛关注。与传统的抗生素相比,AMPs具有不易产生耐药性、低毒性、生物多样性和直接攻击性的特点,AMPs被认为是后抗生素时代最有前途的新一代抗菌药物。目前已有60多种AMPs药物进入市场,数百种AMPs药物正处于临床试验阶段。文章综述了抗菌肽的来源、作用机制及在临床上的应用。

Abstract: Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are usually small peptides composed of 7~100 amino acids, which are an important part of the natural immune defense system. AMPs have many biological activities, such as broad-spectrum anti-infective bacteria (G+, G), antiviral, antifungal, antiparasitic, antitumor and immunomodulatory activities. AMPs can inhibit and kill pathogenic bacteria through membrane acting mechanism and non-membrane acting mechanism. AMPs have been widely concerned in recent years because of their potential therapeutic effects. Compared with traditional antibiotics, AMPs are not easy to produce drug resistance, low toxicity, biodiversity and direct attacking properties. AMPs are considered to be the most promising new generation of antibacterial agents in the post antibiotic era. At present, more than 60 AMPs drugs already reached the market and hundreds of novel therapeutic AMPs are in the clinical trials. This paper reviews the sources, mechanism and recent clinical application of antimicrobial peptides.

1. 引言

抗菌肽(Antimicrobial peptide, AMPs)又叫宿主防御肽(Host defence peptide, HDPs),通常是由7~100个氨基酸组成的小分子多肽 [1],是生物体天然免疫防御系统的一个重要组成部分 [2],也是各种生物抵御入侵病原体的第一道防线 [3]。AMPs具有广谱抗感染性细菌(G+、G) [4]、抗病毒 [5]、抗真菌 [6]、抗寄生虫 [7]、抑杀肿瘤细胞 [8] 和免疫调节 [9] 等生物学活性。尽管大多数AMPs是阳离子肽,但在脊椎动物、无脊椎动物和植物中已经发现了一些阴离子AMPs (Malik等,2016) [10]。根据AMPs的二级结构,AMPs可分为四大类:1) α-螺旋(α-helical)、2) β-折叠(β-Stranded)、3) β-发夹或环(β-hairpin or loop)和4) 延伸型肽(extended),其中α-螺旋肽和β-折叠肽是最常见的(图1) [11]。本文就抗菌肽的来源、作用机制及在临床上的应用作一综述。

(a) α-螺旋(α-helix)、(b) β-折叠(β-strand)、(c) β-发夹或环状(β-hairpin or loop)、(d)延伸型(extended)

Figure 1. The secondary structural classes of antimicrobial peptides. Adapted from Ahmed T A E, Hammami R. (2019)

图1. AMPs的二级结构。引自Ahmed T A E, Hammami R. (2019)

2. 抗菌肽的来源

AMPs的发现可以追溯到1939年,当时,Dubos从土壤样本的芽孢杆菌(Bacillus)中分离出一种抗菌剂 [12],这种物质能预防小鼠肺炎球菌(Pneumococcus)的感染,后来被命名为gramicidin (短杆菌肽) [13]。此后,从原核生物和真核生物中相继发现了许多AMPs [14] [15] [16],仅蛙皮肤中就发现了300多种AMPs [15]。据APD抗菌肽数据库报道(截止2020年5月),已经有3099种天然抗菌肽被鉴定、分离出来,其中来自于动物2359种(76.12%)、植物352种(11.36%)、细菌355种(11.46%)、真菌20种(0.65%)、原虫8种(0.26%)、古细菌5种(0.16%) [17] (见图2)。表1总结了从各种生物中发现的部分AMPs。

Figure 2. The sources of AMPs. Adapted from http://aps.unmc.edu/ap/main.php (May, 2020)

图2. AMPs 的来源。引自http://aps.unmc.edu/ap/main.php (2020年5月)

Table 1. Some antimicrobial peptides from various organisms

表1. 各种生物来源的部分抗菌肽

注:F——真菌;G+——革兰氏阳性菌;G——革兰氏阴性菌。

3. 抗菌肽的作用机制

一般来说,AMPs首先通过静电作用与细菌细胞膜相互吸引 [66]。根据其作用方式,AMPs的作用机制可分为膜作用和非膜作用两种类型。

3.1. 膜作用机制

阳离子AMPs通过选择性相互作用与带负电的微生物外膜作用(Zhao等,2001 [67];Sani等,2016 [68]),导致细胞膜破裂而引起细胞内物质的渗漏而杀死细胞(Da Costa 等,2015 [69])。这些AMPs在与微生物细胞膜相互作用的过程中显示出结构和拓扑的动态性变化(Mingeot-Leclercq等,2016 [70];Haney等,2017 [71])。目前,解释AMPs作用于细菌膜的机制,有桶板模型(barrel-stave model)、环形孔模型(toroidal-pore model)、地毯模型(carpet-like model) 聚合模型(aggregate model)。如图3所示(Nguyen等,2011 [72])。

A桶板模型(barrel-stave model)、B环形孔模型(toroidal-pore model)、C地毯模型(carpet-like model)、D聚集模型(aggregate model)

Figure 3. The membrane acting mechanisms following initial adsorption of AMPs. Adapted from Nguyen, et al. (2011) and Da Costa, et al. (2015)

图3. AMPs初始吸附后作用于细胞膜的机制。引自Nguyen等(2011)和Da Costa等(2015)

3.1.1. 桶板模型(Barrel-Stave Model)

在该模型中,α-螺旋结构的AMPs与细胞膜结合后,促使更多的AMPs结合在细胞膜表面,AMPs由与细胞膜平行方向逐渐转为垂直方向,通过螺旋结构中的疏水区域,插入至磷脂双分子层中,形成“桶样”的穿膜通道(Yang等,2001 [73];Reddy等,2005 [74])。更多AMPs分子的聚集增大了孔径,导致细胞内容物的外溢,最终导致细胞死亡(Brogden,2005 [75])。

3.1.2. 环形孔模型(Toroidal-Pore Model)

在环形孔模型中,AMPs的亲水段与细胞膜中磷脂的极性部分相互作用,并持续诱导脂质单层弯曲以获得稳定的曲率并形成环形孔(Melo等,2009 [76])。当插入的AMPs的极性面与膜脂的极性头结合时,形成跨膜环形孔,孔内同时排列着肽和脂头基团(Brogden, 2005 [75])。

3.1.3. 地毯式模型(Carpet Model)

在该模型中,AMPs与靶膜表面结合,并以地毯状的形式覆盖。在AMPs达到特定阈值后,肽分子与磷脂头基结合,形成含有碎片的胶束而穿透膜(Melo等,2009 [76]),最终导致细胞膜崩解和随后的细胞死亡(Gaspar等,2013 [77])。

3.1.4. 聚合模型(Aggregate Channel Model)

在该模型中,AMPs无特定取向地聚集在细胞膜表面,达到一定浓度后与膜磷脂分子形成类似胶状的肽–脂复合物,以类似洗涤剂的方式破坏脂质双层,形成跨膜的动态孔道(Wu等,1999 [78])。

3.2. 非膜作用机制

一些AMPs即使在低浓度下,也不改变膜完整性,穿过膜脂质双层,靶向细胞内成分(Hancock等,2002 [79]),通过影响细胞内代谢活动,如结合DNA,阻断酶活性,抑制DNA、RNA或蛋白质的合成等而杀死细菌(Cudic等,2002 [80];Krizsan等,2014 [81];Mansour等,2014 [82];Yeaman等,2003 [83]。见图4 (Da Costa等,2015 [69])。表2列出了部分作用于细胞内活性的抗菌肽。

Figure 4. The non-membrane acting mechanisms of AMPs. Adapted from Da Costa, et al. (2015). A. Disruption of cell membrane integrity); B. Blocking of RNA synthesis); C. Inhibition of enzymes necessary for linking of cell wall structural proteins; D. Inhibition of ribosomal function and protein synthesis; E. Blocking of chaperone proteins necessary for proper folding; F. Targeting of mitochondria: 1) inhibition of cellular respiration and induction of ROS formation, 2) disruption of mitochondrial cell membrane integrity and efflux of ATP and NADH

图4. AMPs非膜作用机制。引自Da Costa等(2015)。A. 破坏细胞膜完整性;B. 阻断RNA合成;C. 抑制细胞壁结构蛋白连接所需酶的活性;D. 核糖体功能与蛋白质合成的抑制;E. 适当折叠所必需的伴侣蛋白的阻断;F. 靶向线粒体:1) 抑制细胞呼吸和诱导活性氧(ROS)的形成,2) 破坏线粒体膜完整性以及ATP和NADH的外排

Table 2. Some antimicrobial peptides acting on intracellular activity

表2. 部分作用于细胞内活性的抗菌肽

4. AMPS在临床上的应用

4.1. AMPS作为治疗局部感染的药物

目前,一些抗菌肽已用于治疗人的局部感染药物,如抗菌肽NEUPREX为rBPI21的注射制剂,用于治疗接受心脏直视手术的儿科患者和严重烧伤患者(Conlon, 2011) [90];重组肽HBD-2用于治疗在使用假体植入过程中获得的感染(Shin, 2013) [91];来源于两栖动物皮肤的肽,如白细胞介素(alyteserin)、灯盏花素(brevinin)、蛔虫毒素(ascaphin)、假丝酵素(pseudin)、卡氏菌素(kassinatuerin)和颞叶蛋白(temporin),已被有效地用于治疗由鲍曼不动杆菌(Acinetobacter baumannii)、肺炎克雷伯菌(Klebsiella pneumoniae)、大肠杆菌(Escherichia coli)、金黄色葡萄球菌(Staphylococcus aureus)、铜绿假单胞菌(Pseudomonas),念珠菌(Candida spp.)等多重耐药菌株引起的局部感染(Migoń, 2018) [92];P113是另一种天然存在于唾液中的抗菌肽(Haney, 2018) [93],它以漱口液的形式用于治疗艾滋病毒(HIV)患者的口腔念珠菌病(Candidiasis)感染。Pexiganan用于治疗糖尿病足溃疡中的局部感染(Greber, 2017) [94];吲哚基肽的变体MX-226和MX-594AN (omiganan pentahcolitan,1%凝胶)分别用于治疗与使用导管相关的感染和治疗寻常痤疮(Sachdeva, 2017) [95]。

4.2. 临床试验中的AMPs

目前,超过60种AMPs药物投入市场,数百种新的治疗用AMPs正处于临床试验中(Lau, 2018) [96] (见表3)。新出现的多肽技术,包括多功能肽、细胞穿透肽和肽–药物结合物,将拓宽AMPs在医学中的应用(Raucher, 2015) [97]。

Table 3. Partial AMPs in clinical trials

表3. 临床试验中的部分AMPs

5. 总结

抗生素耐药性是世界第二大死亡原因,导致每年约70万人死亡,预计到2050年每年死于抗生素耐药性的人数将达到1000万,造成的经济损失约10万亿美元。抗生素耐药性是多方面、多层面的,革兰氏阳性菌和革兰氏阴性菌都对现有的抗菌药物产生了难以治愈的耐药性,如耐万古霉素的粪肠球菌(Enterococcus faecium)、阴沟肠杆菌(Enterobacter cloacae, MRSA),耐碳青霉烯类的鲍曼不动杆菌(Acinetobacter baumannii)和耐第三代头孢菌素大肠杆菌(E. coli)、β-内酰胺酶的MDR菌株,耐碳青霉烯类铜绿假单胞菌(Pseudomonas aeruginosa)和分枝杆菌(Mycobacterium)。对碳青霉烯类抗生素耐药的肺炎克雷伯菌(Klebsiella pneumoniae)对美国批准用于治疗的26种抗生素均产生耐药性。抗生素耐药性在全球范围内的扩展和蔓延速度远远高于发现并最终批准用于临床的新抗生素的速度。目前已有相当部分的AMPs在临床应用或处于临床试验中。AMPs被认为是后抗生素时代最有前途的新一代抗菌药物。人们对AMPs的结构、理化性质以及对其活性的影响已有充分的了解,但对AMPs的作用机制以及其对细菌和宿主细胞的反应仍缺乏深入了解。这是未来AMPs在临床上普遍应用的主要瓶颈。

文章引用: 吴阳开 , 金明昌 (2020) 抗菌肽的来源、作用机制及临床应用研究进展。 临床医学进展, 10, 1729-1942. doi: 10.12677/ACM.2020.108260

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