AMB Advances in Microbiology 2327-0810 Scientific Research Publishing 10.12677/AMB.2024.131002 AMB-82710 AMB20240100000_32625734.pdf 生命科学 植物激素水杨酸在微生物中的功能与作用机制 The Biological Functions of Plant Hormone Salicylic Acid in Microbes and the Underlying Molecular Mechanisms 李 林 1 * 宋 凯 1 2 何 亚文 1 2 上海交通大学生命科学技术学院，微生物代谢国家重点实验室，教育部代谢与发育科学国际合作 联合实验室，上海 null 01 02 2024 13 01 14 27 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

水杨酸是一种重要的植物激素，参与植物的生长、发育和防御反应。最近研究表明，水杨酸及其衍生物阿司匹林对环境微生物、肠道微生物和病原微生物也具有生物学功能。本文系统综述了水杨酸对多种微生物的影响，包括抑制某些微生物的生长和复制、影响微生物的代谢及毒力因子的表达、提高微生物对部分抗生素的敏感性、诱导某些微生物内在的多重抗生素耐药表型；同时对水杨酸的这些生物学功能背后的分子机制进行了探讨。这些研究结果有助于我们全面认识水杨酸的生物学功能，为更深入的研究提供理论指导。 Salicylic acid (SA) is an important plant hormone and is involved in plant growth, development and defense. Recent findings revealed that SA and its derivative such as Aspirin also have biological functions on environmental microbes, gut microbes and pathogenic microbes. This review summarized the effects of SA on these microbes, including inhibiting the growth and replication of certain microbes, affecting microbial metabolism and expression of virulence factors, increasing microbial sensitivity to certain antibiotics, and inducing the intrinsic multi-antibiotic resistance phenotype of certain microbes. This review also explored the molecular mechanisms underlying the SA-regulated functions. These findings represent a more comprehensive understanding of the role of SA and provide theoretical guidance for further research.

 水杨酸，微生物，生物学功能，分子机制, Salicylic Acid Microbes Biological Function Molecular Mechanism 摘要

水杨酸是一种重要的植物激素，参与植物的生长、发育和防御反应。最近研究表明，水杨酸及其衍生物阿司匹林对环境微生物、肠道微生物和病原微生物也具有生物学功能。本文系统综述了水杨酸对多种微生物的影响，包括抑制某些微生物的生长和复制、影响微生物的代谢及毒力因子的表达、提高微生物对部分抗生素的敏感性、诱导某些微生物内在的多重抗生素耐药表型；同时对水杨酸的这些生物学功能背后的分子机制进行了探讨。这些研究结果有助于我们全面认识水杨酸的生物学功能，为更深入的研究提供理论指导。

 关键词

水杨酸，微生物，生物学功能，分子机制

 The Biological Functions of Plant Hormone Salicylic Acid in Microbes and the Underlying Molecular Mechanisms<sup> </sup>

Lin Li, Kai Song, Ya-Wen He

Joint International Research Laboratory of Metabolic and Developmental Sciences, State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University (SJTU), Shanghai

Received: Jan. 15th, 2024; accepted: Mar. 6th, 2024; published: Mar. 18th, 2024

 ABSTRACT

Salicylic acid (SA) is an important plant hormone and is involved in plant growth, development and defense. Recent findings revealed that SA and its derivative such as Aspirin also have biological functions on environmental microbes, gut microbes and pathogenic microbes. This review summarized the effects of SA on these microbes, including inhibiting the growth and replication of certain microbes, affecting microbial metabolism and expression of virulence factors, increasing microbial sensitivity to certain antibiotics, and inducing the intrinsic multi-antibiotic resistance phenotype of certain microbes. This review also explored the molecular mechanisms underlying the SA-regulated functions. These findings represent a more comprehensive understanding of the role of SA and provide theoretical guidance for further research.

Keywords:Salicylic Acid, Microbes, Biological Function, Molecular Mechanism

Copyright © 2024 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

水杨酸(Salicylic Acid, SA)或2-羟基苯甲酸(2-Hydroxybenoic Acid)是植物产生的一种酚类激素(图1)，参与植物的生长、发育和防御等生理过程 [ 1 ] 。长期以来，SA在两方面的生物学功能受到广泛的关注：一是SA参与植物防御病原菌侵染的分子机制与信号通路。近期，水杨酸甲酯(图1)也被报道是植物间赖以通讯的信号分子，这一发现又将植物激素SA的研究推向了一个新高度 [ 2 ] 。二是SA衍生药物乙酰水杨酸(阿司匹林；Aspirin；ASA)在临床上的应用。然而，越来越多的研究表明，SA对环境微生物、肠道微生物与病原微生物也具有生物学功能。本文系统总结了SA对这些微生物的影响和作用机制，为进一步深入研究SA的生物学功能提供思路。

图1. 水杨酸、水杨酸甲酯、水杨苷和阿司匹林结构式

 2. 水杨酸的发现及其药物应用

根据文献记载，公元前4世纪，古苏美尔人和埃及人就开始使用柳树和杨树等植物的树皮和叶子治疗疼痛、发烧及炎症；18世纪后期，英国牧师Edward Stone证实柳树枝具有解热效果；1824年，意大利维罗纳的两位药剂师Francesco Fontana和Bartolommeo Rigatelli首次提取了柳树皮的有效成分，命名为水杨苷(salIcin) (图1)；1838年，意大利化学家Raffaele Pirìa获得了纯化的水杨酸，确定其分子式C7H6O3[ 3 ] 。

1859年，德国化学家Hermann Kolbe与其助理Rudolf Wilhelm Schmitt联合建立了Kolbe-Schmitt反应，化学合成了水杨酸；1897年，拜耳公司的化学家Felix Hoffmann合成了乙酰水杨酸，Arthur Eichengrun通过临床试验证实了该化合物的药效，并将其命名为“阿司匹林” [ 4 ] 。此后，阿司匹林广泛应用于疼痛、风湿热和风湿性关节炎等炎症性疾病的治疗。直至今天，阿司匹林仍然是临床上使用最多的药物之一，除了作为镇痛药和解热药外，阿司匹林还用于预防和治疗心脏病、冠状动脉问题和脑血栓，对结直肠癌、肝癌、肺癌等癌症也具有预防作用 [ 5 ] 。

 3. 植物中SA的合成途径、功能及其信号通路

水杨酸在植物体内的生物合成途径主要包括异分支酸(Isochorismate; IC)途径和苯丙氨酸解氨酶(Phenylalanine Ammonia Lyase, PAL)途径 [ 6 ] ，前者为植物中SA合成的主要途径。拟南芥中 IC途径主要包括异分支酸合酶ICS (Isochorismate Synthase)、转运蛋白EDS5 (Enhanced Disease Susceptibility5)和氨基转移酶PBS3 (avrPphB Susceptible3)。ICS负责将分支酸异构化为异分支酸 [ 7 ] ；EDS5是定位于叶绿体包膜上的多药和毒素外排家族转运蛋白，负责将异分支酸从质体(叶绿体)转运到胞质中；PBS3催化谷氨酸与异分支酸结合产生异分支酸-9-谷氨酸(IC-9-Glu)，IC-9-Glu自发分解成SA和2-羟基丙烯酰基-N-谷氨酸 [ 8 ] 。植物也可以通过PAL将苯丙氨酸转化为反式肉桂酸(Trans-Cinnamic Acid, t-CA)，t-CA可转化为邻香豆酸，再进一步转化为SA；t-CA也可以被转化为苯甲醛、苯甲酸(BA)，再在苯甲酸羟化酶(Benzoic Acid 2-Hydroxylase)的作用下转化为SA [ 9 ] 。

1979年，White等首先报道水杨酸诱导烟草对烟草花叶病毒产生抗性，并诱导病程相关蛋白(Pathogenesis-Related Protein，PR蛋白)的积累 [ 10 ] 。经过30多年的研究，最近的研究结果确认SA通过NPR1诱导多种PR蛋白的表达，并参与调节植物系统获得性抗性(SAR)、病原相关分子模式触发的免疫(PTI)、效应触发免疫(ETI)，抵抗病原菌的侵染 [ 11 ] 。此外，SA对植物的抗逆能力及生长发育也有不同程度的影响。例如，SA影响植物对干旱、重金属毒性、高温和渗透胁迫等非生物胁迫的耐受性；SA还可以影响种子萌发、根的发育、细胞生长、呼吸、衰老等相关基因表达 [ 12 ] 。

 4. 细菌中SA的生物合成途径与代谢通路

据报道，多种细菌都能合成SA或其相关代谢物，特别是植物根际促生假单胞菌和芽孢杆菌以及部分人类致病菌，如沙门氏菌、嗜铬杆菌、弧菌、耶尔森氏菌和分枝杆菌 [ 13 ] [ 14 ] 。部分植物内生假单胞菌、短小杆菌等也可以合成SA [ 15 ] 。细菌中水杨酸的生物合成主要有两条途径。一是两步酶法，以假单胞菌属和芽孢杆菌属细菌为代表，首先通过异分支酸酶将分支酸转化为异分支酸，再通过异分支酸丙酮酸裂合酶(Isochorismate Pyruvate Lyase, IPL)将异分支酸盐转化为SA和丙酮酸盐(图2) [ 7 ] [ 14 ] 。另一条途径是一步酶法，存在于结核分枝杆菌、小肠结肠炎耶尔森氏菌和鼠疫耶尔森菌等致病性细菌中，该途径依赖一个双功能的水杨酸合成酶(Salicylate Synthase, SAS)，SAS具有环异构化和丙酮酸裂解酶活性，可直接将分支酸转化为SA (图2) [ 14 ] 。

SA在细菌体内代谢机理研究不多，在铜绿假单胞菌中的研究结果相对比较深入。铜绿假单胞菌包含一个pchABCDEFGHI基因簇，其中两个相邻基因pchAB (分别编码IPL和ICS)负责合成SA。合成的SA继续作为前体，经过PchCDEFGHI的催化生成螯铁蛋白(Pyochelin, PCH) (图3) [ 17 ] 。鳌铁蛋白是可以螯合铁离子的铁载体，帮助细菌在环境铁浓度非常低的情况下吸收铁离子；鳌铁蛋白–铁复合物还可以引起宿主急性感染、氧化损伤和炎症反应，是细菌致病的关键因素 [ 18 ] 。

目前认为，细菌在铁元素有限的条件下合成水杨酸，并以水杨酸为前体合成儿茶酚盐类铁载体，帮助细菌获取铁营养 [ 19 ] ，或作为一种竞争机制，抑制其它微生物生长，也可作为毒力因子对抗宿主免疫系统 [ 20 ] 。此外，SA可在细菌中羟基化产生儿茶酚、儿茶酚甲酸(2,3-DHBA)及龙胆酸(2,5-DHBA)，儿茶酚和儿茶酚甲酸可以在一种以上的酶的催化下转化为水杨酸衍生的铁载体；儿茶酚和龙胆酸也可在TCA途径中代谢(图2) [ 14 ] 。在一些假单胞菌属中，也报道了以SA为前体合成的抗生素Promysalin [ 21 ] 。

图2. 细菌中SA及其衍生物儿茶酚酸铁载体的生物合成途径 [ 14 ]

图3. 铜绿假单胞菌pch基因簇及鳌铁蛋白生物合成路径 [ 16 ]

 5. 水杨酸影响细菌的生理生化功能 5.1. SA影响大肠杆菌的耐药性及生物膜的形成

大肠杆菌是肠道中的正常寄居菌，能竞争性抵御致病菌的进攻，合成维生素K2等，与人体互利共生。在机体免疫力降低、肠道长期缺乏刺激等特殊情况下，大肠杆菌可以移居到肠道以外的地方，造成相应部位的感染，变成机会致病菌。随着阿司匹林的广泛应用，SA及其衍生物对大肠杆菌的影响受到广泛关注，尤其是对SA对大肠杆菌的耐药性影响。由于阿司匹林在体内会迅速降解为SA，因此本综述尽可能使用了SA的数据。SA能够通过激活MarRAB操纵子增强大肠杆菌外排泵AcrAB的表达、降低外膜孔蛋白OmpC、OmpF、OmpX的表达，导致了大肠杆菌抗生素耐药性的增强 [ 22 ] [ 23 ] ；也有研究发现SA能通过提高膜电位来增强大肠杆菌对氨基糖苷类抗生素的敏感性 [ 24 ] 。

SA对大肠杆菌生物膜的形成也有影响。生物膜是附着在表面或界面上生长并嵌入自产细胞外基质中的复杂微生物群落 [ 25 ] ，对杀菌剂的抵抗力比浮游生物高出几个数量级 [ 26 ] 。生物膜形成是一个动态过程，第一步是细菌通过菌毛粘附到表面。Kunin等人最先提出SA能够阻断大肠杆菌中鞭毛蛋白的合成 [ 27 ] ；接着Kang等观察到SA显著抑制肠聚集性大肠杆菌的聚集粘附、菌毛表达和血凝作用 [ 28 ] ；Vila等研究认为SA通过激活大肠杆菌转录调节因子MarA、降低菌毛粘附因子编码基因fimA和fimB的表达来减少生物膜的形成 [ 29 ] ；Cattò等发现SA可以抑制大肠杆菌的细胞粘附和生物膜结构发育、从而抑制大肠杆菌生物膜的形成，是一种潜在的生物膜分散剂；进一步研究发现SA还影响生物膜内细胞的氧化应激水平，SA处理的生物膜的细胞内活性氧(ROS)显著增加 [ 30 ] ，但其潜在的分子机制仍然未知；Uhlich等发现SA可以增强大肠杆菌转录因子pchE的表达，pchE能够减少大肠杆菌生物膜的形成和其对宿主细胞的粘附，但水杨酸抑制大肠杆菌的生物膜并不通过pchE [ 31 ] 。

 5.2. SA影响人类与动物病原细菌的生长、耐药性和致病性

水杨酸衍生药物阿司匹林在临床上常与抗菌药物联合使用以提高治疗效果。研究发现，水杨酸对多种病原细菌的生长、代谢、抗生素的敏感性或耐药性及毒力因子表达等方面均有显著影响。

5.2.1. SA抑制病原细菌生长

水杨酸可以抑制多种动物病原细菌的生长，包括幽门螺杆菌弯曲菌、幽门螺杆菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌、表皮葡萄球菌等，水杨酸(部分实验使用阿司匹林)对这些病原细菌的最低抑菌浓度(Minimal Inhibitory Concentrations, MICs)介于0.05~3.20 mg/ml [ 32 ] 。

 5.2.2. SA影响病原细菌耐药性

阿司匹林能够增强幽门螺杆菌对抗菌药物阿莫西林、克拉霉素和甲硝唑的敏感性 [ 33 ] 。进一步研究发现阿司匹林提高了幽门螺杆菌外膜的通透性，进而提高了细胞内甲硝唑浓度。因此，阿司匹林可能通过改变外膜蛋白(OMP)的表达而增加细胞内抗菌剂浓度，增强幽门螺杆菌对甲硝唑的敏感性 [ 34 ] 。SA也能够抑制鲍曼不动杆菌外排泵AdeB、AdeR及外膜孔蛋白OprD的表达量，进而增强病原菌对头孢曲松、环丙沙星、庆大霉素等抗生素的敏感性 [ 35 ] 。

SA也会诱导部分细菌外排泵的表达量提高，从而对一些抗生素产生更强的耐药性。例如：在SA存在的条件下，铜绿假单胞菌 [ 36 ] 、洋葱伯克氏菌 [ 37 ] 、肺炎克雷伯氏菌 [ 38 ] 、鼠伤寒沙门氏菌 [ 39 ] 等细菌对β-内酰胺类、碳青霉稀类、喹诺酮类、四环素类等抗生素的耐药性显著增强；粘质沙雷菌对氨苄西林、头孢噻肟和头孢他啶的耐药性提高2~4倍，对头孢西丁的耐药性提高20倍 [ 40 ] ；空肠弯曲杆菌对氟喹诺酮类 [ 41 ] 、氯霉素、红霉素、四环素等抗生素的耐药性提高2倍左右 [ 42 ] [ 43 ] 。

 5.2.3. SA影响病原细菌毒力因子的产生

据研究报道，SA对多种细菌毒力因子的产生均有显著影响 [ 44 ] 。细菌毒力因子有助于细菌在宿主中侵染和定殖，常见的毒力因子包括：粘附素、分泌系统及其分泌的效应蛋白、外毒素、生物膜、群体感应分子等 [ 45 ] 。其中，群体感应是目前研究的较多的SA的可能作用靶标之一，群体感应(Quorum Sensing, QS)指微生物通过分泌和感应信号小分子来感应自身所处的群体密度，调控基因表达的一种通讯联络机制，是微生物侵染宿主、提高群体竞争能力的一种保守机制 [ 46 ] [ 47 ] 。

铜绿假单胞菌一种革兰氏阴性机会致病菌，常见于患有囊性纤维化和人类免疫缺陷病毒的免疫功能低下患者。铜绿假单胞菌包含两套酰基高丝氨酸内酯类群体感应系统：LasI/LasR和RhlI/RhlR，调节毒力相关基因的转录 [ 48 ] 。SA处理导致铜绿假单胞菌lasI和lasR水平分别抑制了3倍和2倍，并抑制了铜绿假单胞菌毒力蛋白和蛋白酶的产生，显著下调了QS调节基因和毒力基因的表达 [ 49 ] 。此外，铜绿假单胞菌还是一种臭名昭著的生物膜生产菌，SA可以通过抑制QS相关基因的表达及减少绿脓菌素、鼠李糖脂等的产生来抑制铜绿假单胞菌生物膜的产生 [ 50 ] [ 51 ] ，可以有效降低该菌的毒力。

金黄色葡萄球菌是一类革兰氏阳性病原细菌，通过AgrC/AgrA双组分系统感应群体感应信号，调控致病因子表达，研究报道SA处理显著下调金黄色葡萄球菌AgrC和AgrA的表达，抑制Agr群体感应信号的产生 [ 52 ] 。金黄色葡萄球菌也可以通过形成生物膜引发慢性感染，SA处理降低了金黄色葡萄球菌乌头酸酶的活性，刺激其形成生物膜的乳酸发酵途径，促进金黄色葡萄球菌形成生物膜 [ 53 ] ；并通过干扰AGR群体感应信号的表达，阻止细菌从生物膜扩散到宿主的不同部位，但是可能导致细菌在寄主局部建立感染的持久性增加 [ 52 ] 。此外，也有报道SA通过降低α-溶血素基因启动子hla和纤连蛋白基因启动子fnbA的表达，来减轻金黄色葡萄球菌的两种重要毒力表型：α-溶血素分泌和体外纤连蛋白结合，从而降低金黄色葡萄球菌的体内毒力 [ 54 ] 。

表皮葡萄球菌是人体皮肤上常见的共生微生物，同时也是一种重要的机会性病原菌，在临床上被认为是留置医疗器械上最常见的感染源。研究表明SA处理可以降低表皮葡萄球菌对聚合物的粘附性，减少表皮葡萄球菌细胞外粘液的产生 [ 55 ] ；SA还通过减少磷壁酸、黏液相关蛋白、多糖等生物膜成分的产生来抑制表皮葡萄球菌生物膜的产生 [ 56 ] 。

此外，SA还被报道可以抑制荧光假单胞菌的生物膜形成，但其中大部分研究只局限于观察到SA抑制了生物膜形成的早期粘附步骤，并没有进一步对真实环境中生物膜的复杂性进行进一步的探究 [ 57 ] 。

 5.3. SA影响植物病原细菌的群体感应机制和致病因子

SA作为一种植物防御激素，在植物抵抗病原菌的侵染中发挥非常重要的作用。寄主植物受病原菌侵染部位的SA局部浓度在叶片组织中可以达到150~300 μM，在韧皮部分泌物中可以达到600 μM [ 58 ] [ 59 ] 。植物病原细菌在植物体内或体表繁殖，不可避免地暴露在侵染部位高浓度SA环境中。因此，研究SA对植物病原细菌的影响具有非常重要的意义。

野油菜黄单胞菌(Xanthomonas campestris pv. Campestris, Xcc)是十字花科植物黑腐病的病原菌，黑腐病是一种在全球范围内发生的危害较大的植物病害，因此Xcc也被列为分子植物病理学十大植物病原菌之一 [ 60 ] 。Song等发现SA可以直接作用于Xcc的QS系统，诱导群体感应信号BDSF和DSF降解；进一步研究发现SA诱导野油菜黄单胞菌BDSF和DSF的降解并不是通过直接影响基因表达，而是通过抑制细菌胞内外pH值的下降来提高RpfB (QS信号分子DSF降解酶)的酶活性，Song等由此提出宿主植物和病原菌之间通过SA信号进行相互作用的模型：Xcc病原相关分子模式(PAMP)由位于植物细胞膜中的受体(R)蛋白感测；进而激活植物中的SA生物合成途径；SA渗透或运输到Xcc中，并由假定的SA传感器感测；随后SA信号通路改变了Xcc中的质子动力(PMF)，影响相关外排泵的功能，导致培养物和细胞质pH值升高，进而提高RpfB酶活性，从而诱导DSF降解，最终影响细菌毒力(图4) [ 44 ] 。

胡萝卜软腐果胶杆菌(Pectobacterium carotovorum, Pcc)是肠杆菌科的植物病原菌，可引起多种水果、观赏植物和蔬菜的软腐病，导致田间和储存中的严重农业损失 [ 61 ] 。Joshi等报道SA通过抑制胡萝卜软腐果胶杆菌expI (编码QS信号合成酶)和expR (编码QS信号受体蛋白)的表达，干扰AHL群体感应信号的产生，影响QS调节基因及其他毒力基因的表达 [ 62 ] ；并通过分子对接模拟进一步发现，SA可以直接结合胡萝卜软腐果胶杆菌ExpI蛋白来抑制AHL的产生 [ 63 ] 。

图4. SA诱导DSF群体感应信号降解的分子机制模式图 [ 44 ]

迪基氏菌(Dickeya)是另一类引起植物软腐病的肠杆菌科病原菌，在世界各地的作物和观赏植物中造成严重病害，已成为农业生产的主要威胁 [ 64 ] 。近年来研究发现，SA可以抑制玉米迪基氏菌III型分泌系统相关基因的表达(尤其是主调控基因hrpL)，减轻玉米迪基氏菌对非寄主烟草叶片的超敏反应及对寄主植物的软腐病症状 [ 65 ] 。

根癌农杆菌(Agrobacterium tumefaciens)是一类宿主广泛的土传细菌，能够将其肿瘤诱导质粒中的T-DNA(转移DNA)转移并整合到植物中，从而引起多种植物的冠瘿病 [ 66 ] 。研究发现，SA在酸性条件下可以上调根癌农杆菌attKLM基因簇的表达，降解AHL群体感应信号，导致群体感应信号衰减和农杆菌毒力降低 [ 67 ] 。更有趣的是，SA可以抑制根癌农杆菌vir毒力基因的表达，而根癌农杆菌在完成感染后，则通过调节因子SghR及水解酶SghA利用植物激素SA重新编程自身毒力基因表达 [ 68 ] 。

 6. SA影响病原真菌的生长与发育

水杨酸很早就被广泛用作抗皮肤真菌剂的主要成分，研究认为SA主要通过引起细胞内部酸化，影响胞内某些关键酶的表达来实现其抗真菌活性 [ 69 ] 。许多研究报道，SA对白色念珠菌、尖孢镰刀菌、葡萄顶枯病菌和扩张青霉菌等均具有抗菌活性。

白色念珠菌(Candida albicans)是一种常见的条件致病菌，可引起免疫功能低下患者的一系列感染，由于其可以产生生物膜，对临床使用的多种抗真菌药物具有抗性 [ 70 ] 。阿司匹林能够抑制白色念珠菌生物膜形成，在体外具有显著的抗生物膜活性 [ 71 ] 。Carvalho等研究还发现阿司匹林抑制了白色念珠菌中天冬氨酸蛋白酶的分泌，减少了念珠菌中生物膜与天冬氨酸蛋白酶相关的致病行为 [ 72 ] 。

扩张青霉菌(Penicillium expansum)是一种非常具有侵略性的真菌，可导致严重的苹果蓝霉病，能够迅速传播并产生对人体有害的霉菌毒素 [ 73 ] 。Da Rocha Neto等报道SA抑制青霉菌的孢子萌发，具有抗真菌活性；且SA的抑菌效果受pH影响，在pH £ 3时抑菌效果较好，对扩张青霉的抑制可达100%，但在较高的pH值下会逐渐丧失抑菌活性；SA还会破坏真菌细胞质膜，导致病原菌蛋白质渗漏到培养基中，造成脂质损伤和细胞内紊乱 [ 74 ] 。

尖孢镰刀菌(Fusarium oxysporum)是破坏性非常大的一类土传病原菌，被评为世界第五大植物病原真菌，引起番茄、棉花和香蕉等多种作物的枯萎病，造成严重损失 [ 75 ] 。Wu等发现SA可以显著抑制尖孢镰刀菌菌丝生长、孢子形成和分生孢子萌发 [ 76 ] ；Li等进一步研究发现，SA通过激活FoSNF1 (FoAMPKa)，进而磷酸化FoRAPTOR，抑制FoTORC1信号通路(FoTORC1正向控制生长和毒力基因的表达)，导致尖孢镰刀菌菌丝生长、孢子产生和毒力受阻(图5) [ 77 ] 。与此同时，内源性水杨酸羟化酶(FoSAH1)显著减轻外源性SA的毒性，FoSAHs的多样性也是尖孢镰刀菌能够成功在多种寄主植物中定殖和存活的主要原因之一 [ 77 ] 。

图5. SA抑制尖孢镰刀菌的分子机制示意图 [ 77 ]

Eutypa lata是引起葡萄顶枯病的真菌中致病力最强的一种，寄主范围广泛，可侵染80多种木本植物。Amborabé等观察到SA处理抑制了Eutypa lata的菌丝生长，并在不同细胞区室(细胞壁、线粒体、液泡和细胞核)上观察到菌丝体的结构组织发生了变化，菌丝变成类似中空的结构 [ 78 ] 。

 7. SA影响病毒的复制与侵染

Spier等人最早于1998年报道了水杨酸盐(阿司匹林和水杨酸钠)具有抗病毒作用，他们研究发现阿司匹林处理减少了人巨细胞病毒感染冠状动脉平滑肌细胞的复制 [ 79 ] 。此后，有关水杨酸盐的抗病毒作用相继报道：水杨酸盐可以抑制黄病毒的复制，减少黄病毒触发的细胞凋亡 [ 80 ] ；还可以抑制流感病毒 [ 81 ] 、丙型肝炎病毒的复制 [ 82 ] ；并可以阻断丙型肝炎病毒的细胞进入 [ 83 ] 。

Rivas-Estilla等报道阿司匹林可用作抗丙型肝炎病毒(HCV)药物，并对水杨酸盐抑制丙型肝炎病毒的代谢机制进行了一系列研究(图6)。一方面，阿司匹林可以降低丙型肝炎病毒的RNA和病毒蛋白水平，激活细胞p38丝裂原活化蛋白激酶(MAPK)和丝裂原活化蛋白激酶/细胞外信号调节激酶1/2 (MEK1/2) [ 82 ] 。另一方面它具有抗氧化作用，通过下调环氧合酶2 (COX-2)的表达、诱导铜锌–超氧化物歧化酶(Cu/Zn-SOD)表达，降低细胞氧化应激的产生 [ 84 ] 。此外，一氧化氮合酶(iNOS)在阿司匹林介导的HCV表达下调也发挥了作用，阿司匹林通过下调启动子活性、mRNA和蛋白水平来降低iNOS的表达，同时降低HCV的表达 [ 85 ] 。Yin等报道了一种新的机制，认为阿司匹林通过蛋白酶体途径降解Claudin-1，从而抑制HCV进入细胞 [ 83 ] 。

图6. ASA诱导HCV表达下调的可能机制 [ 85 ]

水杨酸盐对其他病毒产生抑制的代谢机制也有部分报道，例如在流感病毒中，SA通过抑制病毒基因表达相关的转录因子核因子-κB (NF-κB)的表达来阻断流感病毒的传播 [ 81 ] ；在黄病毒中，SA抑制其感染并不依赖于阻断NF-kB途径，而是通过激活p38丝裂原活化蛋白激酶(MAPK)来抑制黄病毒 [ 80 ] 。

 8. 结论

本文综述了目前关于SA对微生物在生长、代谢、毒力和侵染中的生物学作用，包括抑制微生物复制和生长、改变毒力因子表达、抑制或促进细菌耐药性、影响群体感应系统及生物膜的产生等。SA的双重身份，决定了它长期以来都是抗病领域研究的热点之一。一方面，SA作为“明星药物”，其潜在应用价值还有待进一步发掘。在抗生素耐药性泛滥成灾和新抗生素难以开发的时代，探索基于SA对细菌耐药性的影响，开发新的抗菌药物治疗效果尤为重要。另一方面，SA作为“第六类”植物激素，不仅在植物免疫、信号交流中发挥着非常重要的作用，同时也在植物病原真菌、病原细菌的生长、代谢、侵染中扮演重要角色，在未来农业生产中可以被进一步开发为绿色生物农药，既能够防治病害发生、抵抗各种植物病原菌的侵染，也能够促进植物生长、协助植物抵抗各种生物胁迫和非生物胁迫。有鉴于此，未来有必要加强SA在各种微生物中的作用机制研究。

 基金项目

国家自然科学基金(31972231、32172355)。

 文章引用

李 林,宋 凯,何亚文. 植物激素水杨酸在微生物中的功能与作用机制The Biological Functions of Plant Hormone Salicylic Acid in Microbes and the Underlying Molecular Mechanisms[J]. 微生物前沿, 2024, 13(01): 14-27. https://doi.org/10.12677/AMB.2024.131002

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