摘要
SaeRS双组分调控系统是金黄色葡萄球菌(Staphylococcus aureus)中重要的调控系统,因其能够协调多种毒力因子的表达和生物被膜形成,并介导严重致病性而被广泛深入研究。SaeRS系统通过传感器组氨酸激酶SaeS识别外部信号,并通过调节SaeR的磷酸化状态来激活其功能,而辅助蛋白SaeP和SaeQ在该系统中发挥着增强功能的作用,帮助细菌逃避宿主免疫应答。此外,S. aureus的其他调控系统及调节因子可协同SaeRS系统参与毒力表达调控,进一步增强细菌的致病性。本文综述了SaeRS系统及其与其他调控系统和因子相互作用以调控毒力因子表达和生物被膜形成的机制,总结了针对SaeRS系统的靶向药物,并分析了抗SaeRS系统药物的具体实例以协助筛选和设计新的靶向药物,为SaeRS系统的具体调控机制研究以及S. aureus相关感染的治疗提供参考。
金黄色葡萄球菌(Staphylococcus aureus)作为常见的革兰氏阳性致病菌,广泛分布于人类和动物的皮肤、鼻腔及肠道等部位。耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)的出现,使得S. aureus在全球范围内广泛流行,对公共卫生安全构成了严重威胁。溶血素、凝固酶、中毒性休克综合征毒素-1 (toxic shock syndrome toxin 1, TSST-1)等毒素以及侵袭性酶等是导致S. aureus致病性的主要毒力因子。S. aureus生物被膜的形成会显著加剧皮肤、软组织、血液等部位的感染,进而引发脓毒血症、中毒性休克综合征、肺炎等疾病。其中,SaeRS是调控S. aureus毒力因子和影响生物被膜形成的关键双组分系统;研究表明,该系统能够与其他调控系统/因子发生交互作
1 SaeRS系统概述
SaeRS双组分系统由sae操纵子调控,包含saeP、saeQ、saeR、saeS四个基因,以及P1、P3两个启动

图1 SaeRS双组分调控系统
Figure 1 SaeRS two-component regulatory system. A: Regulatory mechanisms of the SaeRS system; B: Three-dimensional predicted structure of the SaeS protei
SaeS由跨膜、HAMP和激酶3个结构域组
SaeS作为响应外界信号的重要蛋白,其激酶活性已被证
SaeR的蛋白结构已经被成功解析(
辅助蛋白SaeP和SaeQ并不直接参与激活SaeRS系统,但它们需要通过形成SaePQS三元复合物来诱导SaeS的磷酸酶活
总之,SaeRS系统的激活依赖于SaeS识别信号及SaeR磷酸化目标基因,而SaePQ主要协助SaeS识别和传导信号。然而,各个组件之间具体的调节机制和界限目前尚不清楚。
2 影响SaeRS系统的信号
2.1 激活信号
HNP1-3是人中性粒细胞产生的抗菌肽,为吞噬溶酶体中的主要抗菌活性物质。Geiger
钙卫蛋白是中性粒细胞中的另一种蛋白,它与Zn结合能够使SaeRS系统不受Zn和Fe的抑
2.2 抑制信号
目前,脂肪酸被认为是抑制SaeRS系统表达的主要信号分子之一。脂肪酸通过抑制SaeS跨膜结构域的18氨基酸结合位点活性,从而实现对毒力因子表达的抑
3 SaeRS系统与其他调控系统和因子的关系
目前已经发现多种调控系统和因子与SaeRS系统之间存在着极为复杂的交互关系,影响着S. aureus的生物被膜形成、毒力因子表达等各种生理活

图2 saeS、saeR与其他基因的相互作用网络预测
Figure 2 Prediction of interaction network between saeS, saeR, and other genes. A: Interaction network prediction of saeS with other genes; B: Interaction network prediction of saeR with other genes.

图3 与SaeRS系统互作的调控因子
Figure 3 Regulatory factors that interact with the SaeRS system.
3.1 SarA
SarA作为全局转录调控因子,在S. aureus的毒力因子表达、生物被膜形成和环境信号转导中发挥关键作用。saeRS和sarA之间存在协同作用,能够共同抑制细胞外蛋白酶的产生,并协助积累生物被膜形成的关键蛋
3.2 CodY
CodY是一种转录调控因子,能对营养物质的变化做出响应,进而调节S. aureus的代谢以及毒力因子的表达。CodY通过调控S. aureus细胞膜上支链脂肪酸的合成,从而激活SaeS并升高SaeR磷酸化水平,促使SaeRS系统的表
3.3 Agr
Agr系统作为一个关键调控系统,对S. aureus的生存、致病性以及抗生素耐药性等具有重要作用。由于agr突变后降低了sae P1、sae P3启动子的活性,以及SaeRS系统mRNA的表达水平,研究者认为SaeRS系统位于Agr调控细胞外蛋白产生途径的下
3.4 ScrA
ScrA是一种新发现的小蛋白,它通过SaeRS系统影响S. aureus的毒力因子表达。当ScrA过表达时,会导致SaeRS系统的调控活性增强;但在调节溶血活性时,ScrA似乎独立于SaeRS系统发挥作
3.5 其他调控系统/因子
Rho是一类小GTP酶,参与细菌的信号传导等过程。当S. aureus的Rho蛋白被抑制时,SaeRS系统可表现出更高活性,从而调控靶基因表
PurN可影响S. aureus的代谢途径和毒力因子表达,对持留菌形成和毒力具有重要调控作用,能够与谷氨酸合酶GltB相互作用,激活SaeRS系统以调节S. aureus毒
ClpXP蛋白酶复合体在S. aureus中发挥蛋白质降解和应激响应的功能,它通过影响FtsH的稳定性和降解MoeA蛋白,间接影响SaeRS系统的功
总之,深入了解这些调控网络机制对于理解S. aureus如何适应宿主环境并引发疾病具有重要意义。这些调控因子与SaeRS系统的相互作用,揭示了S. aureus在复杂的宿主环境中生存和致病的策略。通过进一步研究这些调控机制,可为开发新的治疗方法和抗菌策略提供重要的理论依据。
4 SaeRS系统对细菌生理活动的影响
4.1 对关键毒力因子表达的影响
SaeRS系统通过调控SaeR的磷酸化状态来影响下游目标基因的表达。根据SaeR的磷酸化水平,即目标基因所需的激活条件,可将下游目标基因分为2类。I类目标基因(如coa、fnbA、eap、sae等)需要高水平的磷酸化SaeR来激活;而II类目标基因(如hla、hlb、cap等)仅需低水平的磷酸化SaeR即可激
S. aureus是溶血素一类具有重要生物活性的蛋白质,能够破坏红细胞膜并损伤白细胞。溶血素可分为α-溶血素、γ-溶血素等5种,其中α-溶血素是研究最为广泛的溶血素。研究表明,SaeRS系统能够正向调控由hla编码的α-溶血素和hlb编码的β-溶血
TSST-1是S. aureus产生的外毒素,能够导致宿主发生休克、多器官功能障碍综合征等急性疾病。SaeRS系统是TSST-1主要的转录激活因子,SaeR直接结合到tst启动子上的共识别结合位点,从而激活TSST-1的表达;同时,saeS的突变可导致TSST-1的表达完全丧
凝固酶(由coa编码)在S. aureus的自我防护以及逃避免疫中发挥重要作用,是SaeRS系统调控的侵袭性酶之
核酸酶(由nuc编码)同样是S. aureus重要的侵袭性酶之一,它参与了对抗宿主免疫反应的过程。SaeRS系统调控nuc的表达不仅影响S. aureus的侵袭性,还可能影响其逃避宿主免疫的能力。在SaeRS系统中,SaeP能够通过SaeRS系统下调nuc-gfp基因的表
SaeRS系统还参与了S. aureus部分表面结构蛋白表达的调节。在SaeRS系统的调控下,fnbA基因编码的纤维连接蛋白结合蛋白A协助了生物被膜的形成。SaeS的不同亚型对fnbA的调控存在差异,Sae
综上所述,毒力因子作为S. aureus生理活动过程中重要的组成部分,为其入侵宿主发挥了关键作用。尽管SaeRS是毒力调控的重要系统,然而其他调控因子也参与其中,使得S. aureus的毒力调控机制显得极为复杂。这种多基因之间的相互作用为S. aureus在感染过程中适应不同环境以及逃避免疫系统攻击提供了多种策略。
4.2 对生物被膜形成的影响
S. aureus的生物被膜由胞外多糖、蛋白质、胞外DNA和脂质等组成,是细菌适应环境和获取营养的结构基础。它可提高S. aureus的耐药能力、造成慢性感染、协助免疫逃逸、引起宿主组织破坏等。因此,生物被膜是S. aureus引起严重感染疾病的重要因素之一。研究已经发现,saeS的突变可导致SaeRS系统处于持续活化状态,从而抑制了生物被膜的形
SaeRS系统能够通过感知营养物质水平(如S. aureus外毒素和蛋白酶导致宿主细胞裂解释放的营养物质)来调控毒力基因,从而协助形成生物被
Barraza
总之,SaeRS系统通过直接或间接调控多个与生物被膜形成相关的基因和蛋白质,以及与其他调控网络的交互作用,共同调控S. aureus的生物被膜形成。这为理解S. aureus如何利用其复杂的调控网络适应环境压力和宿主防御提供了重要视角,并为开发针对S. aureus生物被膜形成的新型治疗策略提供了潜在目标。
4.3 对免疫逃逸的影响
鉴于SaeRS系统对毒力因子和生物被膜的调控作用,S. aureus在入侵宿主后可能以此逃避免疫系统的识别、杀伤、清除,帮助S. aureus进一步扩散感染。例如,S. aureus可通过分泌毒力因子来损伤中性粒细胞和巨噬细胞,以抵抗吞噬作用,中性粒细胞作为机体清除S. aureus的主要免疫细胞之一,其释放的HNP等抗菌物质却可激活S. aureus的SaeRS系统信号响
S. aureus的宿主免疫逃逸机制为其生存和扩散提供了重要途径,这也加大了治疗S. aureus感染的难度。因此,深入了解宿主信号激活SaeRS系统的机制,包括信号分子的种类、信号分子与SaeRS系统的作用方式以及免疫逃逸方式,将有助于研究制定针对S. aureus的免疫逃逸应对策略。这对于有效控制S. aureus感染、提高治疗效果具有重要的现实意义。通过揭示这些机制,可以更好地理解S. aureus与宿主免疫系统之间的相互作用,为开发新的治疗方法和疫苗提供理论依据。
5 靶向SaeRS系统的药物
SaeRS系统在S. aureus毒力因子表达和生物被膜形成过程中发挥着重要作用,是极具潜力的有效抗菌靶点。因此,筛选或设计靶向SaeRS系统的药物成为众多研究者的关注热点,目前也已相继发现并鉴定出一些靶向SaeRS系统的药物(
Drug | Usage phase | Structural formula | Target | Research phase | References |
---|---|---|---|---|---|
Repurposed fenoprofen | Clinical use phase |
![]() | SaeR; sae P1 | In vivo |
[ |
Floxuridine |
![]() | sae P1; Phla |
[ | ||
HR3744 | Laboratory research phase |
![]() | SaeR |
[ | |
SAV13 |
![]() | ||||
Phenazopyridine hydrochloride | Clinical use phase |
![]() | SaeS | In vitro |
[ |
Xanthoangelol B1 | Laboratory research phase |
![]() |
[ | ||
20S-ginsenoside Rg3 |
![]() | SaeRS system |
[ | ||
Gambogic acid |
![]() | In vivo |
[ | ||
Neogambogic acid |
![]() |
(待续)
研究发现,由美国食品和药物管理局(United States Food and Drug Administration, FDA)批准用于抗炎的非甾体药物非诺洛芬可靶向SaeR,它通过抑制sae P1启动子和SaeR,使SaeR无法结合下游DNA介导的目标基因表达,最终导致S. aureus的毒力因子表达下降,生物被膜形成受到抑制且结构被破坏,该作用在小鼠模型中得到了验证,且对临床菌株有
力。目前,非诺洛芬、盐酸非那吡啶等已应用于临床的药物在S. aureus感染的治疗方面展现出潜在的应用前景。因此,后续研究可针对这些药物开展临床抗感染试验评估,以便进一步确定其疗效和安全性。然而,在进行临床评估时需充分考虑这些药物已知的其他药理作用,谨慎评估其对其他组织器官可能产生的不利影响,确保在治疗感染的同时不会引发其他不良反应。此外,深入挖掘传统药物资源对加速新型药物的开发和利用具有重要意义,这将为应对耐药菌感染等临床难题提供更多的解决方案。
为了有效筛选或设计靶向抑制SaeRS系统的药物,我们借助ChEMBL数据库对靶向SaeRS系统的药物展开了生物信息学分析。
Serial number | A | B |
---|---|---|
Structural formula |
![]() |
![]() |
Molecular | 426.51 | 408.49 |
AlogP | 4.32 | 4.91 |
Polar surface area | 118.22 | 97.99 |
HBA | 6 | 5 |
#ROS violations | 0 | 0 |
HBD (lipinski) | 5 | 4 |
CX acidic pKa | 7.66 | 6.93 |
CX logp | 4.69 | 5.85 |
Aromatic rings | 2 | 2 |
QED weighted | 0.29 | 0.27 |
Molecular weight (monoisotopic) | 426.204 2 | 408.193 7 |
#Rotatable bonds | 10 | 9 |
Molecular species | Neutral | Neutral |
HBD | 5 | 4 |
HBD (lipinski) | 6 | 5 |
#ROS violations (lipinski) | 0 | 0 |
CX basic pKa | - | - |
CX logD | 4.50 | 5.23 |
Heavy atoms | 31 | 30 |
Np likeness score | 1.89 | 1.93 |
A is source drug basic information based on bioinformatics analysis; B is Xanthoangelol B1 basic information. - indicate that neither drug has an accurate CX basic pKa (acid dissociation constant) value, possibly due to its structural complexity or low solubility.
6 总结与展望
S. aureus在全球范围内的流行已造成了严重的公共卫生问题。
S. aureus的毒素(如溶血素、TSST-1等)、侵袭性酶(如凝固酶、核酸酶等)、表面蛋白等致病因素是S. aureus在宿主体内感染和增殖的重要手
另一方面,SaeRS系统并非独立地调节S. aureus的毒力因子和生物被膜,它与其他调控系统和调控因子形成了一个复杂的调控网络。Ro
作者贡献声明
吴钰煌和乐贤:论文撰写和修改;张庆勇:文献收集和绘图;邹黎黎和陈围:论文指导和审阅。
利益冲突
作者声明不存在任何可能会影响本文所报告工作的已知经济利益或个人关系。
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