微生物学通报  2021, Vol. 48 Issue (4): 1249−1259

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文章信息

张玲娜, 董丽, 廖红梅
ZHANG Lingna, DONG Li, LIAO Hongmei
细菌响应过量活性氧的存活策略及相关研究进展
Survival strategies of bacteria in response to excessive reactive oxygen species: a review
微生物学通报, 2021, 48(4): 1249-1259
Microbiology China, 2021, 48(4): 1249-1259
DOI: 10.13344/j.microbiol.china.200636

文章历史

收稿日期: 2020-06-22
接受日期: 2020-08-21
网络首发日期: 2020-11-09
细菌响应过量活性氧的存活策略及相关研究进展
张玲娜1 , 董丽2 , 廖红梅1     
1. 江南大学食品学院    江苏  无锡    214122;
2. 中国农业大学食品科学与营养工程学院    北京    100083
摘要: 活性氧(Reactive Oxygen Species,ROS)是指基态氧分子获取电子后形成的一类具有高反应活性的物质。有氧呼吸电子传递链产生的内源ROS能维持细菌正常生理活性,而由消毒、抗生素和物理场等处理产生的外源ROS会随着处理时间和强度增加而累积产生。过量ROS会给细菌带来氧化压力,导致氧化损伤,甚至影响其活性。本文综述了过量ROS诱导细菌氧化应激反应并以非芽胞状态存活,阐述过量ROS与特殊状态的形成、复苏或修复甚至死亡过程的关联性,以期为有效控制腐败菌和致病菌的技术创新提供理论基础。
关键词: 细菌    活性氧    氧化损伤    存活策略    
Survival strategies of bacteria in response to excessive reactive oxygen species: a review
ZHANG Lingna1 , DONG Li2 , LIAO Hongmei1     
1. School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China;
2. College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
Abstract: Reactive oxygen species (ROS) refers to a category of highly reactive substances formed by ground-state oxygen molecules acquiring electrons. ROS can be generated by aerobic respiration electron transport chain that helps maintain normal physiological activity of bacteria. Lots of exogenous ROS are generated and accumulated during cleaning and disinfection, medical treatment, etc. Excessive ROS would bring oxidative stress, lead to oxidative damage, and even affect activities of bacteria. In this review, we analyze the oxidative stress response induced by excessive ROS, the correlation between excessive ROS and the formation, recovery or repair of special non-spore status of bacteria, and even leading to their death, to provide reference for the innovation of effective control of spoilage and pathogenic bacteria.
Keywords: bacteria    reactive oxygen species    oxidative stress    survival strategy    

活性氧(Reactive Oxygen Species,ROS)是基态氧分子获取电子形成的一类具有高反应活性的物质,包括氧自由基和部分非自由基物质。其中,氧自由基主要有超氧阴离子(O2)、羟基自由基(·OH)、氢过氧自由基(HO2·)等,非自由基类ROS有过氧化氢(H2O2)、单态氧(1O2)、次氯酸(HOCl)等[1]

ROS对细菌的影响较复杂。细菌的抗氧化系统可应对少量ROS,但过量外源ROS作用于细胞膜甚至进入胞内会影响其活性。正常生理过程会产生少量ROS,是代谢、生理调节必不可少的[1-2]。初期,少量ROS能在细菌中作为信息分子,通过氧化修饰、激活蛋白质与DNA结合以及基因的转录,增加细菌的抗逆能力或维持生长繁殖等生理活动,例如修饰氧化参与细胞分裂、转录调节功能的硫氧还蛋白[3-4]。过量外源性ROS会带来氧化压力,造成氧化损伤,例如大肠埃希菌(Escherichia coli)胞内H2O2浓度始终保持在小于100 nmol/L,但当其胞内浓度大于1 μmol/L时则有毒性[5-6]。细菌为了存活会产生氧化应激反应,可能会通过改变存在状态,进入休眠或半休眠状态存活,若仍无法应对则死亡。

本文主要围绕ROS对细菌产生的氧化压力及其影响,综述氧化应激反应与持留菌(Persister)、活的非可培养状态(Viable but Non-Culturable,VBNC)细菌、L型(L Form)细菌和生物膜(Biofilm)等非芽胞特殊状态的形成、修复或复苏及死亡的相关性,以期为相关研究提供参考。

1 ROS及其对细菌的氧化压力 1.1 ROS来源及途径

细菌中ROS来源有2种:经有氧呼吸电子传递链产生的内源ROS;由消毒、抗生素和物理场处理等产生的外源ROS,如图 1所示。内源ROS主要来源于有氧呼吸中电子传递链,形成途径为:氧气自由扩散进入胞内,由单个电子供体提供电子形成O2,O2在超氧化物歧化酶(SOD)等作用下形成H2O2,随后与金属离子例如Fe2+发生芬顿反应形成·OH[1]。外源ROS经消毒剂、抗生素和物理场处理产生,与医药处理、清洁消毒和食品杀菌等紧密关联,主要产生方式为:添加H2O2、次氯酸等氧化消毒剂,并通过芬顿反应形成·OH[7-8];添加能诱导ROS形成的抗生素,例如妥布霉素[9];超声波、电离辐射等物理场作用能裂解水产生·OH、O2、H2O2和H·[10-11]

图 1 细菌中主要ROS的来源、分布、转化途径、危害以及激活的氧化应激反应 Figure 1 The source, distribution, transformation pathway, harm induced by ROS in bacteria and their oxidative stress response 注:①食品加工、医药消毒和处理等措施能产生外源ROS;② ·OH不能透过细胞膜,但能氧化细胞膜和外膜的脂质和蛋白质;③胞内H2O2通过芬顿反应形成·OH,氧化DNA;④氧化脂质,主要氧化不饱和脂肪酸形成醛类物质;⑤氧化蛋白质,主要氧化含硫、半胱和蛋氨酸;⑥ ROS氧化碱基,造成DNA链交联以及断裂。细菌通过切割、剪切重组的方式进行修复,主要修复酶有甲酰胺基DNA糖基化酶、核酸内切酶IV和内切核酸酶VIII;⑦ ROS氧化蛋白质。细菌通过硫氧还蛋白、谷氧还蛋白和甲硫氨酸亚砜还原酶还原被氧化氨基酸 Note: ① Exogenous ROS produced by food processing, medical disinfection and treatment, etc.; ② ·OH cannot penetrate membrane, but would oxidize lipids and proteins on inner/outer membrane; ③ Intracellular H2O2 translates into ·OH by Fenton reaction, which oxidizes DNA; ④ ·OH oxidizes lipids, mainly oxidizes unsaturated fatty acids to form aldehydes; ⑤ ·OH oxidizes proteins, including sulfur-containing, cysteine and methionine. ⑥ ROS oxidizes nucleobases causing DNA chain crosslinking and breaking. Bacteria repairs them by cutting and recombination with repair enzymes such as foramide DNA glycosylase, endonuclease IV and endonuclease VIII etc.; ⑦ ROS oxidizes proteins. Bacteria repairs oxidized amino acids mainly by thioredoxin, glutaredoxin and methionine sulfoxide reductase

对细菌有影响的主要ROS有O2、H2O2和·OH。在大肠埃希菌中O2平衡态浓度约为0.1 nmol/L[6]。中性条件下,O2难透过细胞膜;酸性条件下可形成HO2.,不带电荷且能透过细胞膜,其渗透系数为9×10−4 cm/s,略低于水的渗透系数3×10–3 cm/s,远高于阴离子渗透系数[12]。O2可迅速氧化脱氢酶家族中含铁硫簇的酶并使酶失活,例如在大肠埃希菌中O2与含铁硫簇的酶的二级反应速率为106−107 L/(mol∙s),可将[4Fe−4S]2+降解为[3Fe−4S]+,并产生H2O2或水,该酶的失活会抑制三羧酸循环和氨基酸的生物合成[11-12]。但O2半衰期短,歧化反应速率约为5×105 L/(mol∙s),在SOD作用下,两分子O2与一分子H+反应并立刻转化成H2O2和O2[14]

H2O2渗透系数为1.6×10−3 cm/s,近似于水,能自由扩散进入胞内[12]。胞内H2O2浓度高于一定程度后,H2O2会氧化能接触到的铁硫簇,例如脱氢酶,将[4Fe−4S]2+降解为[3Fe−4S]+,不产生游离·OH,在大肠埃希菌中反应速率约为103 L/(mol∙s);H2O2能氧化单核亚铁酶的亚铁离子,使酶失活,影响其参与的代谢途径如戊糖磷酸途径[11, 15-16]。此外,H2O2可通过芬顿反应形成高活性·OH。

·OH几乎能与胞内所有分子反应,反应速率快,可达108−1010 L/(mol∙s),其化学反应时间小于l s,生化反应时间为l−l0 s[17]。·OH与细胞膜上不饱和脂肪酸反应引起脂质过氧化,使细胞膜性质发生改变;其氧化产物如醛类物质会损伤蛋白质和DNA,与DNA形成环外DNA加合物,例如与脱氧鸟苷缩合形成α-羟基丙氨酸脱氧鸟苷和γ-羟基丙氨酸脱氧鸟苷,前者能阻断DNA复制,并可能导致碱基G突变成A或T,后者会造成DNA链内和链间交联[18-19]。需注意,胞外的·OH和O2由于带电荷而难以进入胞内[20]

1.2 ROS对细菌的氧化压力

ROS过量或抗氧化能力降低,超过了细菌调节能力,导致氧化还原失衡,会形成氧化压力[1, 21]。ROS氧化含巯基的氨基酸例如硫氨基酸半胱氨酸和蛋氨酸,以及造成不可逆的蛋白质的羰基化[22-24]。ROS氧化不饱和脂肪酸形成丙二醛等醛基化合物,损伤蛋白质以及DNA[18-19]。ROS氧化碱基例如氧化鸟嘌呤形成8-氧-7-氢脱氧鸟嘌呤,插入到DNA链中,变为与腺嘌呤配对,·OH能高度氧化DNA,造成DNA链的断裂、DNA位点突变和双链畸变[25]

细菌主动采取多种氧化应激措施应对氧化压力,例如激活调节子上调抗氧化酶合成和去掉受损生物大分子等[26]。DNA、脂质和蛋白质损伤,细菌有不同的修复方法:启动核苷酸切除、错配修复和DNA双链断裂等机制,保护基因组稳定性[23, 27];通过各种氧化还原酶例如硫氧还蛋白(Trxs)和谷氧还蛋白(Grxs)等修复巯基的氧化[22-24]。但目前未找到脂质过氧化相关修复机制。

1.3 氧化应激反应相关调节子

参与氧化应激反应的调节子主要有OxyR、SoxRS、RpoS和PerR等(图 1)。OxyR氧化应激方式为:直接清除H2O2和过氧化物等,相关基因有katGahpCahpFyhjAhemF;调控并稳定胞内氧化还原电位,相关基因有grxgortrxCdsbG[28]。胞内H2O2浓度达到200 nmol/L时就能激活OxyR[5]。OxyR能感知H2O2和有机过氧化物,激活转录,控制烷基过氧化氢还原酶(AhpCF)、过氧化氢酶G和周质细胞色素c过氧化物酶(无氧分子可用时利用H2O2支持呼吸作用)的合成[29-30]。PerR能调节H2O2造成的氧化压力,在H2O2作用或铁、锰离子缺乏时,PerR会上调抗氧化酶如过氧化氢酶A和AhpCF,清除H2O2和烷基氢过氧化物[31]。SoxRS主要调节O2造成的氧化压力,调节过程由SoxR和SoxS两个调节子介导,SoxR能激活全局调节子SoxS的转录以及目标基因如多药外排泵、转运蛋白、单氧酶和氧化还原酶的表达;SoxS激活多种基因的转录,调节含锰SOD、葡萄糖-6-磷酸脱氢酶、DNA修复核酸内切酶IV、药物外排泵、外膜蛋白F和外膜蛋白W等基因的表达[32-33]

此外,细菌中还存在着一些应激因子,可以调控氧化应激反应。例如,压力应激因子RpoS是RNA聚合酶的一种σ因子,其能识别转录起始位置,使RNA聚合酶结合在启动子上,启动转录,再延伸RNA链[34]。稳定期细菌通过RpoS应对营养不足、活性氧、极端温度和pH等压力[35]。在环境压力下,RpoS被激活,调控基因katExthA (合成核酸外切酶Ⅲ)的表达[36]。IscR是一种铁硫簇传感器,能感知氧化压力和铁硫簇情况[37]

1.4 细菌氧化损伤严重死亡

若氧化应激反应无法解决外源过量ROS,则ROS会与细菌内的脂质、DNA和蛋白质等反应,造成脂质过氧化、酶金属中心氧化和基因突变等氧化损伤,严重时甚至会导致细菌死亡[22]

光敏剂介导的光动力技术处理大肠埃希菌产生大量ROS,而且脂质过氧化、SOD、过氧化氢酶(CAT)、谷胱甘肽和谷胱甘肽巯基转移酶水平显著升高,膜损伤严重,最终导致细菌死亡[38]。有研究表明抗生素杀菌会产生ROS,处理大肠埃希菌时会引起铁硫簇失稳,通过芬顿反应形成·OH来杀菌[39]。超声波或其与热、高压等联合处理杀菌机制是超声波处理产生空穴效应,进而产生自由基(·OH和H·等)达到杀菌目的[10]。含氯消毒剂如HOCl通过损伤DNA达到消毒目的[8]。紫外线如波长为320−400 nm的UVA通过诱导氧化应激,导致蛋白质损伤、生长延迟和能量代谢减少来破坏细胞[40]。需要注意的是,这些报道中的研究对象为革兰氏阴性菌,因此外膜的存在与否可能与ROS杀菌作用有关。

然而也有学者提出卡那霉素或氨苄青霉素等抗生素对大肠埃希菌的杀菌与ROS无关,因为处理中H2O2和胞内游离铁并未增加[41]。有或无氧条件下用诺氟沙星处理大肠埃希菌其存活率无差异,表明死亡率与ROS水平不相关[42]

总之,细菌体内ROS主要是经有氧呼吸电子传递链产生和医药处理、清洁消毒和食品杀菌等处理引入,内源ROS能参与代谢和生理调节,过量的外源ROS会带来氧化压力,造成氧化损伤,严重时甚至会使细菌死亡。为了应对氧化压力,细菌主动采取了多种氧化应激措施,激活氧化应激调节子,去除ROS并修复氧化损伤。

2 细菌氧化应激反应及其所处状态

部分革兰氏阳性菌能通过形成芽胞抵御外界不良条件,但在一些情况下细菌(以革兰氏阴性细菌为主)也会通过形成非芽胞方式存活[43-44]。如图 2所示,在氧化压力作用下细菌能以不同状态存活,主要包括VBNC态、持留菌、L型细菌和生物膜。

图 2 细菌的不同存在状态与氧化应激反应之间的关系 Figure 2 Relationship between different states of bacteria and oxidative stress response
2.1 ROS与持留菌的形成和复苏

持留菌是一类高度耐受抗生素的细菌,可在含致死剂量抗生素的环境下存活,但停止抗生素处理后能恢复生长繁殖[45]。有研究表明持留菌的形成与氧化压力有关。例如,胆汁处理鼠伤寒沙门菌(Salmonella typhimurium)后会诱导持留菌的形成,该处理产生ROS[46]。此外,研究报道水杨酸处理产生的ROS诱导大肠埃希菌持留菌形成,该过程与膜电位降低和代谢水平减弱有关[45]

ROS诱导持留菌形成的机制研究已有进展。研究表明氧化压力可能导致大肠埃希菌DNA损伤,细菌启动SOS机制修复DNA损伤,同时激活毒素和抗毒素机制,从而诱导持留菌形成[47-48]。ROS激活SoxRS,上调多种药物耐药外排泵的表达,药物外排泵能降低抗生素浓度,使大肠埃希菌呈现耐受性的表型[32, 48]。饥饿诱导铜绿假单胞菌形成持留菌,因为饥饿信号(p)ppGpp激活RpoS应激因子,从而增加抗氧化酶的产生,抵御氧化压力,因此持留菌的形成与RpoS应激因子有关[49]。以上表明,ROS损伤DNA,但可通过启动SOS反应和激活SoxRS和RpoS来维持细胞活性,以持留菌的形态存活。

除停止抗生素作用外,持留菌也可在其他特定条件下复苏。已有研究表明抗氧化酶AhpF和外膜蛋白F可促进持留菌复苏:DNA损伤后激活SOS反应能产生膜去极化毒素(TisB),该毒素能诱导大肠埃希菌进入持留状态,而AhpF和外膜蛋白F能特异性地促进该持留菌的复苏[50]。表明持留菌的复苏也与氧化应激水平有关联。

然而过量积累ROS会导致持留菌死亡。研究发现谷氨酸钠和抗生素如利福平的协同会加速三羧酸循环,增加ROS的产生,从而降低细菌对抗生素的耐受性[51]。此外,等离子体预处理能恢复持留菌的敏感性,可以推测预处理产生的ROS对细菌耐药性有影响[52]

综上所述,氧化应激反应中的SoxRS系统、DNA损伤引起的SOS反应和RpoS应激因子参与诱导持留菌的形成,AhpF可促进持留菌复苏,但氧化压力超过耐受程度会使细菌进入更深层的休眠状态甚至死亡。

2.2 ROS与细菌VBNC状态的形成和复苏

2.2.1 VBNC态细菌的形成以及与氧化应激的关系

VBNC状态是指微生物在不利环境中失去繁殖能力,但合适条件下可复苏并恢复可培养性的一种特殊休眠状态[53]。细菌处于VBNC状态时会发生体积缩小、杆状变成球状等现象,细胞壁和细胞膜组成也发生改变,而且该状态下细菌细胞较指数期细胞具有极低的代谢活性[54-55]。有研究认为VBNC态是处于较持留菌更深的休眠状态,但二者并非同一状态[56]

多种方式都能诱导细菌进入VBNC态,大多数都与氧化压力相关,包括氧浓度波动、重金属、食品防腐剂和紫外线处理等[57-58]。前期研究发现,热辅助超声波处理会导致沙门菌部分进入VBNC态;经检测在热辅助超声波处理中主要产生·OH、烷基自由基和氢质子等自由基,进一步分析发现自由基强度与沙门菌VBNC态形成率高度相关并遵循特定规律;此外,加入常见自由基清除剂丙酮酸钠可降低VBNC态形成率,因而从正反两方面证明ROS与VBNC态形成相关联[10, 59]。这也是在本领域首次将外部环境产生ROS与细菌VBNC态形成之间建立定量关系。此外,本课题组发现经H2O2处理后诱导沙门菌进入VBNC态,其CAT、SOD和谷胱甘肽过氧化物酶完全被钝化,而且H2O2处理中自由基强度与VBNC态形成率呈正相关[60]。以上结果表明VBNC态的形成与ROS施加的氧化压力有关。

氧化压力是细菌形成VBNC状态的一个重要因素。VBNC态细菌的形成机制与氧化压力、RpoS调节因子以及外膜蛋白相关,细菌可培养性的丧失可能与氧化压力下蛋白羰基化和抗氧化酶表达下降有关[56-57]。研究表明低温抑制OxyR介导的CAT酶活会导致VBNC态形成[61-62],并且CAT和SOD缺乏都会导致金黄色葡萄球菌(Staphylococcus aureus)进入VBNC态[63]。烷基氢过氧化物还原酶亚基C (AhpC)具有抗氧化作用,而且与细菌可培养性相关[64]。能调控抗氧化酶合成的RpoS抑制细菌VBNC态的诱导[65],但研究发现,处于VBNC状态的阪崎肠杆菌中rpoSompAhfq基因表达量增多[66]。因此RpoS抑制VBNC态形成,但VBNC态菌可能在保持活性时仍需要RpoS的存在。

2.2.2 VBNC态细菌的复苏与氧化应激的关系

在适当条件下,VBNC态菌会复苏且恢复繁殖能力。多项研究表明CAT或其他的ROS清除剂如丙酮酸钠可提高大肠埃希菌和创伤弧菌的可培养性[67-68]。例如,研究表明H2O2诱导的VBNC态沙门菌在含丙酮酸钠的培养基中能复苏[69];通过添加过氧化氢酶也能使VBNC态短乳杆菌复苏[70],表明降低或消除氧化压力会促进VBNC态细菌复苏。

2.3 ROS对L型细菌形成的影响

L型细菌是指无肽聚糖层和缺失细胞壁的特殊状态,是细菌在像抗生素、抗菌因子以及某些理化条件如等离子体处理等不利条件下形成的一种生存状态[71]

已有研究表明L型细菌的形成与ROS有关。例如,L型枯草芽胞杆菌(Bacillus subtilis)的形成受到ROS的影响,而且ROS清除剂可促进L型枯草芽胞杆菌和大肠埃希菌生长[72];等离子体处理大肠埃希菌会产生ROS,同时诱导形成L型[73],L型细菌会调节氧化应激反应得以生存,包括DNA修复途径、毒素-抗毒素模块、药物外排系统以及isc基因,其中,isc基因控制铁硫簇合成,抑制芬顿反应[74];此外,部分L型细菌的形成可逆,当去除应激后L型细菌能重新合成细胞壁并恢复正常,而且革兰氏阴性菌可能更易发生L型逆转[75]。可见外源性过量ROS会引起氧化应激反应,细菌则形成L型从而存活,去除应激条件后能恢复正常形态,但依然需要更多的证据来佐证ROS参与诱导L型的机制。

2.4 ROS对生物膜形成的影响

逆境下细菌会附着于环境表面,通过分泌蛋白、脂多糖以及核酸等物质形成生物膜[76]。生物膜是细菌生存的一种普遍状态,能保护细菌免受外来刺激,赋予细菌抗性,而且大部分生物膜中含有较大比例的持留菌[9]

已有研究表明生物膜的形成与ROS有关,但形成生物膜能抵御氧化压力。有研究表明,烟气中所含ROS或用H2O2处理细菌会导致金黄色葡萄球菌形成生物膜,烟气和H2O2会导致生物膜形成的相关基因在转录水平表达上调,而且清除ROS不利于生物膜形成[77]。然而也有研究表明ROS不利于形成生物膜,将单增李斯特菌(Listeria monocytogenes)的sod基因敲除后,发现生物膜形成受到阻碍,而且形成了更多的ROS,表明SOD作为一种抗氧化酶有助于生物膜的形成[78]。还有研究表明ROS是单增李斯特菌生物膜形成中的潜在信号分子,通过使用氧化酶抑制剂和ROS清除剂抑制ROS,发现ROS的减少促进了生物膜形成[79]。此外,外源性ROS过量也会导致表皮葡萄球菌(Staphylococcus epidermidis)生物膜失去活性,而添加抗氧化剂能起保护作用[80]。因此,外源氧化压力有助于生物膜形成,但清除正常菌株内源性ROS或敲除抗氧化基因会抑制生物膜的形成,可能与内源性ROS参与正常细菌生理活动有关,但ROS过量也不利于形成生物膜。

另外,RpoS也与细菌生物膜的形成有关。RpoS能调控氧化应激反应,并且有助于胞外多糖psl基因的表达,而胞外多糖是生物膜组成成分之一[36, 80]

3 结论与展望

ROS可作为信号分子参与细菌生理活性的调节,但过量ROS会带来氧化压力甚至氧化损伤,迫使细菌形成持留菌、VBNC状态、L型和生物膜等得以存活,该过程中细菌调动氧化应激反应进行调节,如启动SoxRS、OxyR和RpoS等调节子。当氧化压力超过氧化应激水平时则可导致细菌死亡。在医药处理、清洗消杀、加工处理等过程中不可避免会产生ROS,从控制有害细菌的角度来看其存在是一把“双刃剑”:一方面可利用其氧化压力甚至氧化损伤达到有效控制/杀灭有害细菌的目的;另一方面使得细菌以特殊休眠体等状态得以存活并“巧妙”规避检测,这不利于确保医药处理的有效性和食品安全。

目前,一般是通过检测菌落形成情况来判断致病菌或腐败菌的存在,这并不适合一些特殊休眠状态,因而需要快速、有效、直接的定量检测方法。此外,无论从科研角度还是从医药消杀、食品安全的监管层面,对细菌特殊生存状态的重视程度较低,而且其深层次形成机理的研究较少,今后应充分考虑和检测细菌特殊生存状态的存在及其影响,深入研究相关形成机制,系统分析处理中产生的ROS并进行安全评估,以达到有效控制有害细菌,尤其是控制/杀灭致病菌和腐败菌的目的。

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