微生物学报

Vaccine	Antigenic targets	Indications	Phase	Companies	NCT/References
StaphVax	CP5-rEPA+CP8-rEPA	Patients with advanced chronic kidney disease undergoing hemodialysis, infections following cardiovascular surgery, orthopedic prosthetic implants, and healthy volunteers	III	Nabi	NCT00211913 NCT0007121 NCT00211900 NCT00130260 NCT00211965 NCT00211926 NCT00211991
V710	IsdB	Patients undergoing surgical procedures, renal disease requiring hemodialysis	III	Merck	NCT00518687
NDV-3	Als3	Skin and soft tissue infections (SSTIs)	II	NovaDigm	NCT03455309
SA3Ag	CP5, CP8, ClfA	SSTIs	II	Pfizer	NCT01018641
SA4Ag	CP5, CP8, ClfA, MntC	Nasopharyngeal and cutaneous infections; postoperative spinal infections	II	Pfizer	NCT02492958 NCT0238816 NCT01643941
STEBVax	SEB	Toxic shock syndrome (TSS)	I	NINID	NCT00974935
None	Hla, PVL	SSTIs	II	HJF/Nabi	NCT01011335
Brivalent	RLukS-PV, rAT	Healthy individuals	II	Nabi	[76]
SA75	Whole cell vaccine	Recurrent tonsillitis	I	VRIP	[77]
GSK2392103A+ GSK2392105A+ GSK2392106A+ GSK2392019A	CP5, CP8, Hla, ClfA	Healthy individuals	I	GSK	NCT01160172
Recombinant five-antigen Staphylococcus aureus vaccine (rFSAV)	SEB, IsdB, MntC, SpA, Hla	Closed fracture surgery	II	Olymvax	[78]
PENTASTAPH (SA5AG) GSK387858A	CP5, CP8, WTA, PVL, Hla	SSTIs	II	GSK	NCT04420221

Vaccine	Antigenic targets	Indications	Phase	Companies	NCT/References
StaphVax	CP5-rEPA+CP8-rEPA	Patients with advanced chronic kidney disease undergoing hemodialysis, infections following cardiovascular surgery, orthopedic prosthetic implants, and healthy volunteers	III	Nabi	NCT00211913 NCT0007121 NCT00211900 NCT00130260 NCT00211965 NCT00211926 NCT00211991
V710	IsdB	Patients undergoing surgical procedures, renal disease requiring hemodialysis	III	Merck	NCT00518687
NDV-3	Als3	Skin and soft tissue infections (SSTIs)	II	NovaDigm	NCT03455309
SA3Ag	CP5, CP8, ClfA	SSTIs	II	Pfizer	NCT01018641
SA4Ag	CP5, CP8, ClfA, MntC	Nasopharyngeal and cutaneous infections; postoperative spinal infections	II	Pfizer	NCT02492958 NCT0238816 NCT01643941
STEBVax	SEB	Toxic shock syndrome (TSS)	I	NINID	NCT00974935
None	Hla, PVL	SSTIs	II	HJF/Nabi	NCT01011335
Brivalent	RLukS-PV, rAT	Healthy individuals	II	Nabi	[76]
SA75	Whole cell vaccine	Recurrent tonsillitis	I	VRIP	[77]
GSK2392103A+ GSK2392105A+ GSK2392106A+ GSK2392019A	CP5, CP8, Hla, ClfA	Healthy individuals	I	GSK	NCT01160172
Recombinant five-antigen Staphylococcus aureus vaccine (rFSAV)	SEB, IsdB, MntC, SpA, Hla	Closed fracture surgery	II	Olymvax	[78]
PENTASTAPH (SA5AG) GSK387858A	CP5, CP8, WTA, PVL, Hla	SSTIs	II	GSK	NCT04420221

Antibody	Antigenic targets	Phase	Companies
AR-301/Salvecin	Hla	III	Aridis
MEDI4893/AR320	Hla	III	Medimmune
ASN100	Hla and LukGH	II	Arsanis
None	Hla	Primary screening	Trinomab Biotech

Antibody	Antigenic targets	Phase	Companies
AR-301/Salvecin	Hla	III	Aridis
MEDI4893/AR320	Hla	III	Medimmune
ASN100	Hla and LukGH	II	Arsanis
None	Hla	Primary screening	Trinomab Biotech

Compounds	Sources	Mechanism	References
Norwogonin	Scutellaria baicalensis	Targeting AgrA to inhibit Hla production	[20]
Cinnamaldehyde	Cinnamon essential oil	Acting as a β-lactam adjuvant, targeting SarA to suppress Hla via downregulation of mecA	[96]
Citral	Litsea cubeba essential oil	Interfering with the quorum sensing (QS) system to inhibit Hla expression	[97]
Schisandrone	Lignans	Inhibiting Hla expression	[98]
Isosakuranetin	Bergamot	Inhibiting the transcription and expression of Hla via regulation of upstream RNAIII	[99]
Ampelopsin	Ampelopsis grossedentata	Unclear	[100]
Flavone	Edible plants	Unclear	[101]
Echinatin	Licorice	Suppressing the Agr system, thereby inhibiting Hla expression	[102]
Bavachin	Psoralea corylifolia	Inhibiting Hla expression	[103]
7,8-dihydroxyflavone	Various foods	Inhibiting Hla expression	[104]
Hispidulin	Onopordum acanthium	Targeting the AgrAC system	[105]
10-hydroxy-2-decenoic acid (10-HDA)	Royal jelly	Unclear	[106]
Kaempferol	Various plants	Inhibiting Hla expression	[107]
2,3-dehydrokievitone	Lupine root	Inhibiting Hla expression	[108]
Andrographis paniculata lactone	Labdane diterpenoids isolated from the stems and leaves of Andrographis paniculata	Downregulating the transcription of the Hla gene and its highly associated genes (clfA and fnbA) to inhibit Hla expression	[109]
Luteolin	Various plants and foods	Downregulating the hla gene to inhibit Hla expression	[110]
Naringenin	Oak tree	Targeting AgrB to inhibit Hla secretion	[38]
Fisetin	Rhus succedanea	Targeting AgrB to inhibit Hla secretion	[38]
6-ES	Bocconia frutescens	Unclear	[111]
BiochaninA	Red clover, cabbage, and alfalfa	Inhibiting Hla expression	[112]
Epigallocatechin gallate	Green tea	Inhibiting Hla expression and heptamer pore formation	[113]
Lycopene	Tomato	Inhibiting Hla expression	[114]
Myricetin	Vegetables and fruits	Inhibiting Hla expression	[115]
Pilocarpine	Peganum harmala seeds	Inhibiting Hla expression	[116]
Piperine	Black pepper	Inhibiting Hla expression	[117]
Scutellarin	Herbal medicines	Targeting caseinolytic protease P (ClpP) to inhibit Hla	[118]
Emodin	Polygonum cuspidatum	Unclear	[119]
Brazilin	Dried heartwood of Caesalpinia sappan	Targeting SaeR to inhibit Hla	[21]
Isoliquiritigenin	Licorice	Inhibiting Hla expression	[120]

Compounds	Sources	Mechanism	References
Norwogonin	Scutellaria baicalensis	Targeting AgrA to inhibit Hla production	[20]
Cinnamaldehyde	Cinnamon essential oil	Acting as a β-lactam adjuvant, targeting SarA to suppress Hla via downregulation of mecA	[96]
Citral	Litsea cubeba essential oil	Interfering with the quorum sensing (QS) system to inhibit Hla expression	[97]
Schisandrone	Lignans	Inhibiting Hla expression	[98]
Isosakuranetin	Bergamot	Inhibiting the transcription and expression of Hla via regulation of upstream RNAIII	[99]
Ampelopsin	Ampelopsis grossedentata	Unclear	[100]
Flavone	Edible plants	Unclear	[101]
Echinatin	Licorice	Suppressing the Agr system, thereby inhibiting Hla expression	[102]
Bavachin	Psoralea corylifolia	Inhibiting Hla expression	[103]
7,8-dihydroxyflavone	Various foods	Inhibiting Hla expression	[104]
Hispidulin	Onopordum acanthium	Targeting the AgrAC system	[105]
10-hydroxy-2-decenoic acid (10-HDA)	Royal jelly	Unclear	[106]
Kaempferol	Various plants	Inhibiting Hla expression	[107]
2,3-dehydrokievitone	Lupine root	Inhibiting Hla expression	[108]
Andrographis paniculata lactone	Labdane diterpenoids isolated from the stems and leaves of Andrographis paniculata	Downregulating the transcription of the Hla gene and its highly associated genes (clfA and fnbA) to inhibit Hla expression	[109]
Luteolin	Various plants and foods	Downregulating the hla gene to inhibit Hla expression	[110]
Naringenin	Oak tree	Targeting AgrB to inhibit Hla secretion	[38]
Fisetin	Rhus succedanea	Targeting AgrB to inhibit Hla secretion	[38]
6-ES	Bocconia frutescens	Unclear	[111]
BiochaninA	Red clover, cabbage, and alfalfa	Inhibiting Hla expression	[112]
Epigallocatechin gallate	Green tea	Inhibiting Hla expression and heptamer pore formation	[113]
Lycopene	Tomato	Inhibiting Hla expression	[114]
Myricetin	Vegetables and fruits	Inhibiting Hla expression	[115]
Pilocarpine	Peganum harmala seeds	Inhibiting Hla expression	[116]
Piperine	Black pepper	Inhibiting Hla expression	[117]
Scutellarin	Herbal medicines	Targeting caseinolytic protease P (ClpP) to inhibit Hla	[118]
Emodin	Polygonum cuspidatum	Unclear	[119]
Brazilin	Dried heartwood of Caesalpinia sappan	Targeting SaeR to inhibit Hla	[21]
Isoliquiritigenin	Licorice	Inhibiting Hla expression	[120]

靶向金黄色葡萄球菌α-溶血素的防治策略

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孙婷婷 ¹^,² , 王新宇 ¹^,² , 刘洋 ¹^,² , 李應英 ¹^,² , 王宇星 ¹^,² , 徐飞 ¹^,²^,^*

微生物学报 | 综述 2026,66(10): 4661-4678

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微生物学报 |综述 2026 , 66 (10) : 4661 -4678

靶向金黄色葡萄球菌α-溶血素的防治策略

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孙婷婷¹^,², 王新宇¹^,², 刘洋¹^,², 李應英¹^,², 王宇星¹^,², 徐飞¹^,²^,^*

作者信息

^1.中国农业科学院饲料研究所，国家饲料中药物基准实验室，北京

^2.农业农村部动物源细菌耐药性监测重点实验室，北京

通讯作者:

徐飞

作者简介:

作者贡献声明

孙婷婷：负责综述初稿撰写、调查研究；王新宇：提供资源；刘洋：参与文献的整理与筛选；李應英：验证复核参考资料准确性真实性；王宇星：对综述进行润色修改；徐飞：总体构思、主题选择，监督管理，提供该领域内的专业见解和建议。

Prevention and treatment strategies targeting α-hemolysin (Hla) of Staphylococcus aureus

Tingting SUN¹^,², Xinyu WANG¹^,², Yang LIU¹^,², Yingying LI¹^,², Yuxing WANG¹^,², Fei XU¹^,²^,^*

Affiliations

^1.National Feed Drug Reference Laboratories, Institute of Feed Research of Chinese Academy of Agricultural Sciences, Beijing, China

^2.Key Laboratory of Animal Antimicrobial Resistance Surveillance, Ministry of Agriculture and Rural Affairs, Beijing, China

Corresponding Author:

^*E-mail: xufei@caas.cn

出版时间: 2026-10-04 doi: 10.13343/j.cnki.wsxb.20260087

文章导航

摘要

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兼具高致病性和高抗药性的超级细菌是公共卫生领域的重要挑战，金黄色葡萄球菌(Staphylococcus aureus) α-溶血素(α-hemolysin, Hla)是介导其感染的关键毒力因子，也是防控的重要靶点。本文首先回顾了Hla晶体与七聚体孔道结构的特征；继而系统阐明了hla基因座以及Agr系统、Sar蛋白家族、葡萄球菌辅助调节因子双组分系统(Staphylococcal accessory element regulator, SaeRS)和其他辅助调控因子对其表达的多重精细控制；从细胞及宿主受体2个方面揭示Hla的致病机理；最后重点总结了近年来靶向Hla的疫苗、单克隆抗体、天然化合物和纳米颗粒防治策略的研究进展，为金黄色葡萄球菌耐药感染精准预防提供新思路与候选方案。

关键词

金黄色葡萄球菌 / α-溶血素(Hla) / 致病机理 / 防治

Abstract

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The emergence of superbugs with both high pathogenicity and high antimicrobial resistance poses a major challenge to public health. In Staphylococcus aureus, α-hemolysin (Hla) is a key virulence factor mediating infection and thus represents a crucial target for prevention and control. This review first summarized the structural characteristics of Hla in its monomeric crystalline form and heptameric pore assembly. It then systematically delineated the multi-layered and fine-tuned regulation of Hla expression, involving the hla gene locus, the Agr quorum-sensing system, the Sar protein family, the Staphylococcal accessory element regulator (SaeRS) two-component system, and other auxiliary regulators. The pathogenic mechanisms of Hla were further elaborated from the perspectives of both cellular effects and host receptors. Finally, this review summarized recent advances in prevention and treatment strategies targeting Hla, including vaccines, monoclonal antibodies, natural compounds, and nanoparticles, offering new insights and candidate approaches for the precise prevention of drug-resistant S. aureus infections.

Key words

Staphylococcus aureus / α-hemolysin (Hla) / mechanism of pathogenesis / prevention and treatment

引用本文

孙婷婷, 王新宇, 刘洋, 李應英, 王宇星, 徐飞. 靶向金黄色葡萄球菌α-溶血素的防治策略. 微生物学报, 2026 , 66 (10) : 4661 -4678 . DOI: 10.13343/j.cnki.wsxb.20260087

Tingting SUN, Xinyu WANG, Yang LIU, Yingying LI, Yuxing WANG, Fei XU. Prevention and treatment strategies targeting α-hemolysin (Hla) of Staphylococcus aureus[J]. Acta Microbiologica Sinica, 2026 , 66 (10) : 4661 -4678 . DOI: 10.13343/j.cnki.wsxb.20260087

正文

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金黄色葡萄球菌(Staphylococcus aureus)，简称金葡菌，是重要的人畜共感染革兰氏阳性致病菌。它可引起人类多种局部感染(如肺炎、伪膜性肠炎、心内膜炎)及全身性感染(如败血症、脓毒症)^[1]。每年在全球范围内导致难以计数的皮肤感染和数十万至数百万例侵袭性感染^[2]。该菌也是全球菌血症的主要病原之一，发病率居高不下^[3-4]。在畜牧领域，金黄色葡萄球菌同样是关键病原，可引发奶牛临床型与亚临床型乳腺炎，导致产奶量下降、治疗成本增加和感染个体提前淘汰，对畜牧业造成重大经济损失^[5-9]，并伴随一系列动物福利问题^[10-11]，从而构成显著的公共卫生负担^[12]。我国抗生素耐药性形势严峻，金黄色葡萄球菌是导致抗微生物药物耐药性(antimicrobial resistance, AMR)相关死亡的主要病原体之一，其中耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)表现突出^[13]。

金黄色葡萄球菌是重要的人畜共患机会性致病菌。该菌可在健康成人的鼻腔中呈现无症状定植状态，但在免疫功能低下或者屏障破坏时可引发从局部感染到全身脓毒症等多种疾病。不同菌株的毒力因子谱存在显著差异，其致病潜能差异较大。致病性金黄色葡萄球菌可依赖于其分泌的多种毒力因子，包括溶血素、杀白细胞素、肠毒素、凝固酶和耐热核酸酶等，其中溶血素尤为关键^[14]。α-溶血素(α-hemolysin, Hla)在人与动物疾病中的作用已被认识近百年。其发现可追溯至1928年的一次疫苗污染事件^[15]，后经纯化与结构解析，逐步确立了其作为关键成孔毒素(pore forming toxins, PFTs)的地位^[16-18]。金黄色葡萄球菌可产生α、β、γ、δ、ε等多种溶血素，其中Hla是对数生长后期分泌的主要外毒素之一^[19]，但并非所有菌株均产生该毒素，其表达受生长阶段、环境信号及多层级调控网络的精密控制，呈现显著的菌株间和时间差异性。此外，Hla可作为一种水溶性单体分泌，在宿主细胞膜上自我组装形成跨膜β桶状七聚体通道^[20]，可导致多种细胞的裂解死亡^[21]。动物模型研究进一步证实，Hla能破坏大鼠肺组织的气血屏障，且缺失hla基因的菌株在小鼠感染模型中毒力显著减弱^[22-23]。鉴于其在致病过程中的核心作用，Hla已成为研发新型抗感染药物的重要靶点。

本文系统概述Hla的分子生物学特性与致病机理，并重点综述近年来靶向该毒素的疫苗、单克隆抗体、天然化合物及纳米颗粒等防控策略的研究进展，以期为应对金黄色葡萄球菌感染提供新的思路与方案。

1 Hla的分子生物学特性

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1.1 Hla的结构

首个高分辨率三维结构的α-溶血素发表于1996年，Song等^[24]通过X射线晶体学成功对Hla的七聚体跨膜孔道复合物(即毒素在细胞膜上组装后的活性形式)进行结晶，获得了高质量晶体，收集衍射数据，经计算和建模，最终确定原子水平的三维结构，其孔道的结构解析至1.9 Å分辨率(图1)。该结构证实了Hla低聚物的七聚体亚基化学计量比，提示水溶性蛋白质中富含甘氨酸且溶剂暴露的区域，可通过自组装形成具有特定结构的跨膜孔道；同时，该结构也为深入理解β桶型成孔毒素(β-barrel pore-forming toxin)的膜相互作用机制及转运活性原理提供了依据^[24-25]。

1.2 Hla的基因与调控

1.2.1 Hla的基因

1984年，Gray等^[26]首次完成了hla基因及其编码蛋白的全序列测定。该基因座以单拷贝形式定位于金黄色葡萄球菌染色体上，在所测序的菌株中序列高度保守，其编码的蛋白质一级结构展现出近乎完全的氨基酸序列一致性；hla基因座编码产生由293个氨基酸组成的成熟细胞外蛋白，约33 kDa^[27]。成熟的毒素几乎完全由β链组成，几乎无α螺旋结构^[28]。尽管其基因序列与蛋白结构高度保守，但Hla的表达在转录水平上受到一个复杂而精密的调控网络的动态控制，主要包括群体感应系统、Sar蛋白家族以及其他辅助因子等，以此发挥其致病性。

1.2.2 辅助基因调控系统

辅助基因调控系统(accessory gene regulator, Agr)是金黄色葡萄球菌关键的全局调控系统之一，其借助群体感应机制对Hla及其他毒力因子的表达进行调控。随着细菌群体密度的增加，胞外自诱导肽(autoinducing peptide, AIP)的积累浓度逐渐升高，当AIP浓度达到临界阈值时会启动双组分信号转导系统AgrC-AgrA的激活过程：首先AIP与细胞膜上的AgrC蛋白结合，触发AgrC发生自身磷酸化，随后磷酸基团被转移至AgrA蛋白；磷酸化后的AgrA蛋白会结合到Agr基因座上的P2和P3 2个启动子区域，其中P2启动子调控Agr系统自身的表达(维持系统活性)，P3启动子则控制非编码RNA (non-coding RNA, ncRNA)——RNAⅢ的表达；值得注意的是，RNAⅢ也是Agr系统的重要组成部分，它可通过直接结合Hla的mRNA分子起到稳定mRNA结构、促进其翻译过程的作用^[29-30] (图2)。

1.2.3 Sar蛋白家族

葡萄球菌辅助调节(Staphylococcal accessory regulator, Sar)蛋白家族是与Agr系统协同作用的关键转录调控家族，不同成员的作用机制具有显著差异。根据序列与结构特征，该家族可分为3个亚类：单结构域蛋白(SarA、SarR、SarT、SarV、SarX及Rot)、双结构域蛋白(SarS、SarU、SarY)以及与MarR家族高度同源的单结构域蛋白(SarZ、MgrA/Rat及其同源物)^[31]。

SarA是一种分子量约14.7 kDa的DNA结合蛋白^[32]。它是Hla表达的关键正向调控因子，通过直接结合于hla启动子并激活其转录；还能间接结合至Agr系统的P2 (调控agrABCD)和P3 (调控RNAⅢ)启动子区域，增强Agr系统活性；Agr系统激活后产生的RNAⅢ能够稳定hla mRNA并促进其翻译，从而进一步放大Hla的表达^[33-34]。SarR (约13.6 kDa)是与SarA同源但功能相反的负调控因子，其抑制作用可通过竞争性结合实现；此外还可通过抑制Agr系统，SarR结合至Agr系统的P2与P3启动子，抑制agrABCD及RNAⅢ的表达，从而减弱Agr系统对Hla的正向调控^[33,35]。SarS (又称SarH1，约29 kDa)可激活spa基因并抑制hla转录^[35]。SarT为单结构域蛋白，通常受SarA与Agr系统抑制，其激活可上调sarS，进而抑制hla并激活spa；位于sarT邻近位置的sarU编码一双结构域蛋白，其表达受SarT抑制，而SarT本身又受Agr系统抑制；此外，全局调节因子Rot可通过促进sarS转录间接抑制hla^[36]。SarZ则通过调节SarA与Agr系统活性，最终促进hla等毒力因子的表达^[37]。

1.2.4 SaeRS双组分系统

葡萄球菌辅助调节因子双组分系统(Staphylococcal accessory element regulator, SaeRS)是金黄色葡萄球菌中特有的双组分信号转导系统，可调控Hla等毒力因子的分泌。该系统由组氨酸激酶SaeS (感应蛋白)与反应调节蛋白SaeR构成，其编码基因位于包含saeP、saeQ、saeR和saeS的操纵子中；saeR与saeS的表达由位于saeQ编码区内的组成型启动子P3驱动。当细菌感知宿主环境压力信号时，SaeS发生自磷酸化并将磷酸基团转移至SaeR；磷酸化的SaeR可结合于靶基因启动子区，激活包括hla在内的多种毒力因子转录。此外，SaeRS与Agr系统之间存在协同调控关系，共同精细调节Hla的表达水平^[38]。

1.2.5 其他辅助调节因子

σ因子B (sigma factor B, SigB)在应激条件下可被激活，进而启动应激响应基因的表达^[39-40]。SigB可通过与Sar蛋白家族及Agr系统相互作用，调控包括Hla在内的毒力因子表达。研究表明，SigB可下调Hla的表达，帮助细菌在逆境中保存能量；其机制可能包括间接抑制SarA活性，从而在环境压力与毒力表达之间实现平衡^[41]。

全局转录调控因子CodY是广泛存在于革兰氏阳性菌中的全局抑制性调控因子，可感应细胞内支链氨基酸与GTP浓度变化，协调代谢与毒力基因的表达^[42-43]。在金黄色葡萄球菌中，CodY可通过抑制Agr系统及RNAⅢ间接影响多种毒力因子(如杀白细胞素LukF-PV、透明质酸酶)的表达，也可直接调控Hla及荚膜合成相关基因^[42-46]。然而，其具体分子机制仍有待进一步阐明。

2 Hla的致病机理

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2.1 Hla的孔道形成与直接细胞毒性

Hla分泌后可在细胞膜上形成破坏性孔道直接损伤靶细胞，同时靶向免疫细胞并激活过度的炎症反应，二者共同推动感染的进展与组织损伤。

金黄色葡萄球菌分泌的Hla结合于宿主细胞表面后形成跨膜孔道，导致胞内物质外泄及细胞裂解^[47]。该毒素对多种免疫细胞具有直接细胞毒性，可诱发显著炎症反应，并通过破坏上皮-内皮屏障完整性加剧组织损伤^[48]。研究还表明，Hla能够促进革兰氏阴性菌的共感染，加重感染复杂程度^[49]。孔道形成所引发的离子失衡与信号紊乱是Hla致病的重要环节。Ca²⁺内流可激活血小板，导致促凝因子释放，并促使内皮细胞收缩，参与水肿形成^[50]；同时，Ca²⁺内流还能激活内切核酸酶，诱导细胞凋亡^[51]。研究显示，Hla处理可显著增加兔及小鼠内皮细胞通透性，促进金黄色葡萄球菌的组织侵入^[25,52]。

Hla可广泛靶向天然免疫与适应性免疫细胞，引发强烈炎症反应。该毒素能诱导单核细胞、巨噬细胞、T细胞及吞噬细胞等释放多种细胞因子与血管活性物质，加剧局部炎症^[53-54]。特别值得注意的是，Hla可通过激活NLRP3炎症小体促使巨噬细胞与单核细胞分泌白细胞介素-1β (interleukin-1β, IL-1β)，扰乱组织微环境并扩大炎症损伤^[55-56]。在NLRP3基因敲除小鼠模型中，纯化Hla或金黄色葡萄球菌感染所引起的肺部病理损伤、IL-1β释放及中性粒细胞浸润均显著减轻，证实Hla部分依赖NLRP3通路诱导细胞程序性坏死及促炎介质释放^[56]。此外，Hla还可通过调控IL-17A等细胞因子，影响天然免疫与适应性免疫细胞间的信号传导，进一步调控感染免疫应答^[57]。

2.2 Hla与宿主细胞膜的相互作用及受体介导的致病机制

Hla与宿主细胞膜的特异性结合是其发挥毒力的首要步骤，其具体机制长期存在争议，主要集中于直接膜脂质相互作用与特异性蛋白受体结合2种途径^[58]。

Hla可与细胞膜脂质成分直接结合。研究表明，纯化的Hla能在缺乏蛋白受体的人工脂质膜上寡聚成孔，导致囊泡内容物泄漏^[59-64]。结构分析提示，毒素七聚体表面的“边缘-茎缝隙”区域直接参与脂质头部基团相互作用^[65]。消耗胆固醇或添加外源性磷酸胆碱可显著抑制Hla的结合与毒性，且其与鞘磷脂或磷脂酰胆碱的结合效率存在差异，表明结合具有脂质种类与脂相依赖性^[64,66]。此外，Hla可与细胞膜上富含胆固醇和鞘脂的脂筏结构发生相互作用^[58,66]。值得注意的是，缺乏Hla的金黄色葡萄球菌突变株虽能黏附于肺上皮细胞，但其内化效率显著降低。进一步研究发现，Hla能与脂筏中的小窝蛋白-1特异性结合，促进脂筏聚集，从而介导细菌内化^[67]。这表明Hla的脂质结合能力不仅参与孔道形成，也直接促进细菌侵袭。

另一方面，研究证实去整合素金属蛋白酶10 (a disintegrin and metalloproteinase 10, ADAM10)是Hla在哺乳动物细胞上的关键功能性蛋白受体^[52]。Hla与ADAM10的结合不仅介导毒素在膜上的定位及七聚体孔道形成，还可显著上调ADAM10的金属蛋白酶活性^[52,68]；活化的ADAM10可切割E-钙黏蛋白等细胞黏附分子，破坏细胞间黏附连接及肌动蛋白细胞骨架，导致上皮/内皮屏障功能严重受损，促进细菌扩散^[68-70]。如图3所示，目前研究焦点在于厘清ADAM10介导的毒性究竟源于其受体功能促进的孔道形成、孔道引发的下游信号，还是其酶活激活导致的直接切割，或三者的协同作用^[71]。

3 靶向Hla的治疗策略

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金黄色葡萄球菌感染可引起从局部脓肿至菌血症、脓毒症等全身性重症感染，临床治疗主要依赖抗生素。然而，抗生素的广泛使用与滥用导致以耐甲氧西林金黄色葡萄球菌(MRSA)为代表的多重耐药菌株的蔓延，传统抗菌治疗面临严峻挑战。因此，开发不直接杀菌、从而不易引发耐药性选择的抗毒力治疗策略已成为应对耐药金葡菌感染的重要方向。在众多毒力因子中，Hla因其在致病过程中的核心地位而备受关注。鉴于其保守的序列、明确的致病机制以及在感染模型中的关键作用，Hla被视为极具潜力的抗毒力治疗靶点，为开发新型抗金葡菌药物提供了重要方向。

3.1 疫苗研发

疫苗接种旨在通过诱导机体产生特异性主动免疫应答，以预防金黄色葡萄球菌感染^[72]。鉴于其理论上的优越性，针对该菌多种特异性抗原的亚单位疫苗研发已成为重要方向。本文汇总了已进入临床试验阶段的主要金葡菌疫苗候选物^[73-79] (表1)。截至目前，虽有至少12种疫苗进行了早期临床评估，但研发进程充满挑战。例如，StaphVax与V710虽曾进入III期临床，最终均告失败；近期报道显示，重组五价疫苗(recombinant five-antigen Staphylococcus aureus vaccine, rFSAV)与PENTASTAPH (SA5AG/GSK387858A)可能已进入III期研究阶段^[80]。总体而言，尽管已投入大量临床前与临床工作，目前尚无任何金葡菌疫苗成功上市。

作为关键毒力因子，Hla是备受关注的疫苗靶点，但目前尚未有单一靶向Hla的疫苗获批。以Hla突变体HlaH35L为基础的策略显示出潜力：该突变体无毒但保留免疫原性，能在肺炎与皮肤感染模型中提供有效保护^[81-82]。含有Hla_H35L的四价疫苗经单次免疫即可在小鼠模型中减轻肾脏脓肿、腹膜炎及细菌负荷^[83]。进一步，包含Hla_H35L-IsdB融合蛋白的五价疫苗已在多种动物模型(如脓毒症、烧伤、肺炎及骨关节感染)中表现出广谱保护力，据悉已进入III期临床试验^[84]。此外，新型Hla亚单位疫苗AT62也被评估可作为多价疫苗的组分之一^[85]。尽管前景可观，但以Hla为靶点的疫苗研发仍面临诸多挑战，其最终转化成功仍需进一步探索。

3.2 单克隆抗体治疗

单克隆抗体凭借其高特异性与安全性，已成为抗感染治疗的重要策略。针对金黄色葡萄球菌Hla的中和性抗体尤其具有吸引力，主要基于以下优势：Hla蛋白抗原性强，其氨基酸序列在金葡菌中高度保守(98%-100%)；研究表明，针对Hla的抗体能有效保护人肺上皮细胞免受金葡菌感染所致的细胞溶解^[86-87]。因此，以Hla为靶点的单克隆抗体已成为多家医药企业的重点研发方向(表2)^[88-91]。目前，已有多个靶向Hla的中和性单抗进入临床后期研究。其中，全人源单抗MEDI4893 (Suvratoxumab/AR-320)与AR-301 (Salvecin)均已进入III期临床试验，旨在预防或治疗金葡菌引起的肺炎。此外，ASN100是一种双抗体组合(ASN-1与ASN-2)，可同时中和Hla及5种杀白细胞素(HlgAB、HlgCB、LukED、LukSF[PVL]和LukGH)，其II期研究显示了针对金葡菌毒素的广谱中和潜力^[88-91]。

在新型抗体发现方面，噬菌体展示等技术为筛选高亲和力抗Hla抗体提供了有效手段。例如，从Fab文库中筛选出的YG1抗体，以及通过全人源scFv文库鉴定并改造获得的scFv-Fc融合抗体，均在临床前研究中显示出良好的Hla中和活性与感染保护效果^[92-93]。这些研究为开发下一代基于抗体的抗毒力治疗剂奠定了重要基础。

3.3 天然化合物小分子抑制剂

天然化合物及其衍生物作为Hla抑制剂的重要来源，其价值不仅在于相对低廉的获取成本与良好的成药潜力，更在于其化学结构的多样性为靶向Hla的特定功能域(如膜结合区、寡聚化界面)或调控其表达的上游通路(如Agr、Sae系统)提供了丰富的分子探针。早期研究如β-环糊精衍生物提示了通过空间位阻直接物理性阻塞孔道组装的新思路^[87,94-95]。

天然化合物是发现Hla抑制剂的重要资源。Wu等^[30]曾于2019年综述了24个具有抗Hla活性的天然化合物，其作用机制主要包括抑制Hla寡聚化、或通过干扰Agr群体感应系统、Sae双组分系统及RNAⅢ表达来下调Hla的产生。本课题组近年来致力于从天然化合物中筛选金黄色葡萄球菌Hla抑制剂。前期研究中筛选出柚皮素与漆黄素，二者可通过靶向AgrB蛋白进而抑制Hla的分泌。基于此，本文进一步汇总了2019-2025年间报道的新型天然化合物抑制剂(表3)。如表3所示，目前已知的抑制剂主要通过以下途径发挥作用：(1)调控上游信号通路，如抑制Agr系统、SarA或SaeRS；(2)直接作用于Hla蛋白，干扰其折叠或寡聚化过程。

尽管已有多种天然化合物被报道具有抗Hla活性，但该领域仍面临以下关键局限：首先，目前已开展系统研究的化合物种类仍相对有限，相关结构信息与构效关系数据积累不足，制约了其作为Hla抑制剂的深入开发。其次，多数研究仅停留在表型活性验证阶段，化合物发挥抑制作用的具体分子靶点与作用机制尚不明确。此外，部分抑制剂不仅作用于Hla，还可影响其他毒力因子，体现出多靶点特性，然而其协同作用机制及相关调控网络仍有待深入阐明。

3.4 其他

除上述治疗策略，有研究证实模拟细胞膜的人造纳米粒子(例如脂质体)在体外和体内均具有阻断细菌毒素的潜力。成孔毒素是最常见的细菌毒力蛋白，在细菌感染的发病机制中起重要作用；因此，PFT是细菌感染中极具吸引力的治疗靶点。受成孔毒素(pore-forming toxins, PFTs)的成孔过程和机制的启发，有研究设计了一种集成的混合纳米囊泡——红脂质体(red blood cell membrane-liposome, RM-PL)，通过融合天然红细胞(red blood cell, RBC)膜和人工脂质膜实现PFT解毒；当脂质和红细胞膜整合到杂化纳米囊泡结构中时可实现功能互补；红细胞膜赋予RM-PLs解毒能力，而聚乙二醇化脂质膜稳定RM-PLs，大幅提升红细胞膜的解毒效率；以Hla为模型PFT开展的实验证明，RM-PLs不仅能显著降低Hla在体外对红细胞的毒性，还能在体内有效捕获中和Hla，拯救小鼠免受Hla诱导的组织损伤^[121]。甘草酸常被用作药物递送载体，其与低生物利用度的槲皮素形成新型纳米制剂甘草酸-槲皮素复合物(glycyrrhizic acid-quercetin complex, GAQ)，被证明对金黄色葡萄球菌主要毒性因子Hla表现出抗菌和抗溶血活性^[122]。由此可见，纳米治疗策略展现出巨大的应用潜力。

4 总结与展望

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金黄色葡萄球菌及其耐甲氧西林菌株(MRSA)兼具高致病性与耐药性，已成为全球抗生素耐药防控的核心难题。耐药性与致病性密切相关，二者在菌株进化与传播中常伴随发生：MRSA等耐药克隆株在获得耐药基因的同时，通常携带高表达毒力因子；抗生素选择性压力也可经由Agr等全局调控网络影响毒力基因表达。因此，靶向Hla的抗毒力策略可在抑制致病性的同时规避传统杀菌药物的选择压力，为应对耐药与致病的双重挑战提供新的干预思路。目前Hla在结构解析、致病机理研究以及防控治疗策略开发等方面已取得显著进展。然而，针对Hla的深入研究与治疗策略转化仍面临诸多机遇与挑战。首先，需进一步阐明Hla在复杂感染微环境中与其他毒力因子的协同作用机制，以及其与宿主免疫系统互作的精细调控网络。其次，现有抑制剂大多处于临床前研究阶段，尚未有实现规模化生产与临床应用的有效药物。未来研究应致力于利用结构生物学手段解析Hla与抑制剂复合物的三维结构，指导合理化药物设计；开发联合疗法，将抗毒力策略与抗生素联用，在清除细菌的同时中和其毒性，实现协同增效的治疗效果；探索基于纳米技术的靶向递送系统，提高治疗药物的生物利用度和病灶靶向性；关注宿主导向疗法，通过调节宿主对Hla损伤的应答通路减轻组织病理损伤。本课题组长期致力于金黄色葡萄球菌抗毒力策略研究，已在Hla抑制剂筛选、作用机制解析以及构效关系研究等方面取得初步进展，未来将进一步聚焦Hla与宿主受体互作的关键界面，开展基于结构的精准药物设计，并探索与现有抗生素的协同治疗方案。总之，以Hla为靶点的抗毒力治疗，作为传统抗生素疗法的有力补充，有望为应对耐药性金黄色葡萄球菌感染提供全新的、更具潜力的解决方案。

基金

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国家重点研发计划(2023YFD1800902)
中国农业科学院科技创新工程项目(IFR-06)
家畜产业技术体系北京市创新团队项目(BAIC05-2026)

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2026年第66卷第10期

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doi: 10.13343/j.cnki.wsxb.20260087

接收时间：2026-01-28
首发时间：2026-10-13
出版时间：2026-10-04

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收稿日期：2026-01-28
录用日期：2026-04-10

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National Key Research and Development Program of China(2023YFD1800902)

国家重点研发计划(2023YFD1800902)

Agricultural Science and Technology Innovation Program(IFR-06)

中国农业科学院科技创新工程项目(IFR-06)

Livestock Industry Technology Innovation Team in Beijing(BAIC05-2026)

家畜产业技术体系北京市创新团队项目(BAIC05-2026)

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^1.中国农业科学院饲料研究所，国家饲料中药物基准实验室，北京

^2.农业农村部动物源细菌耐药性监测重点实验室，北京

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Vaccine	Antigenic targets	Indications	Phase	Companies	NCT/References
StaphVax	CP5-rEPA+CP8-rEPA	Patients with advanced chronic kidney disease undergoing hemodialysis, infections following cardiovascular surgery, orthopedic prosthetic implants, and healthy volunteers	III	Nabi	NCT00211913 NCT0007121 NCT00211900 NCT00130260 NCT00211965 NCT00211926 NCT00211991
V710	IsdB	Patients undergoing surgical procedures, renal disease requiring hemodialysis	III	Merck	NCT00518687
NDV-3	Als3	Skin and soft tissue infections (SSTIs)	II	NovaDigm	NCT03455309
SA3Ag	CP5, CP8, ClfA	SSTIs	II	Pfizer	NCT01018641
SA4Ag	CP5, CP8, ClfA, MntC	Nasopharyngeal and cutaneous infections; postoperative spinal infections	II	Pfizer	NCT02492958 NCT0238816 NCT01643941
STEBVax	SEB	Toxic shock syndrome (TSS)	I	NINID	NCT00974935
None	Hla, PVL	SSTIs	II	HJF/Nabi	NCT01011335
Brivalent	RLukS-PV, rAT	Healthy individuals	II	Nabi	[76]
SA75	Whole cell vaccine	Recurrent tonsillitis	I	VRIP	[77]
GSK2392103A+ GSK2392105A+ GSK2392106A+ GSK2392019A	CP5, CP8, Hla, ClfA	Healthy individuals	I	GSK	NCT01160172
Recombinant five-antigen Staphylococcus aureus vaccine (rFSAV)	SEB, IsdB, MntC, SpA, Hla	Closed fracture surgery	II	Olymvax	[78]
PENTASTAPH (SA5AG) GSK387858A	CP5, CP8, WTA, PVL, Hla	SSTIs	II	GSK	NCT04420221

Vaccine

Antigenic targets

Indications

Phase

Companies

NCT/References

StaphVax

CP5-rEPA+CP8-rEPA

Patients with advanced chronic kidney disease undergoing hemodialysis, infections following cardiovascular surgery, orthopedic prosthetic implants, and healthy volunteers

III

Nabi

NCT00211913

NCT0007121

NCT00211900

NCT00130260

NCT00211965

NCT00211926

NCT00211991

V710

IsdB

Patients undergoing surgical procedures, renal disease requiring hemodialysis

III

Merck

NCT00518687

NDV-3

Als3

Skin and soft tissue infections (SSTIs)

NovaDigm

NCT03455309

SA3Ag

CP5, CP8, ClfA

SSTIs

Pfizer

NCT01018641

SA4Ag

CP5, CP8, ClfA, MntC

Nasopharyngeal and cutaneous infections; postoperative spinal infections

Pfizer

NCT02492958

NCT0238816

NCT01643941

STEBVax

SEB

Toxic shock syndrome (TSS)

NINID

NCT00974935

None

Hla, PVL

SSTIs

HJF/Nabi

NCT01011335

Brivalent

RLukS-PV, rAT

Healthy individuals

Nabi

[76]

SA75

Whole cell vaccine

Recurrent tonsillitis

VRIP

[77]

GSK2392103A+

GSK2392105A+

GSK2392106A+

GSK2392019A

CP5, CP8, Hla, ClfA

Healthy individuals

GSK

NCT01160172

Recombinant five-antigen Staphylococcus aureus vaccine (rFSAV)

SEB, IsdB, MntC, SpA, Hla

Closed fracture surgery

Olymvax

[78]

PENTASTAPH

(SA5AG)

GSK387858A

CP5, CP8, WTA, PVL, Hla

SSTIs

GSK

NCT04420221

Antibody	Antigenic targets	Phase	Companies
AR-301/Salvecin	Hla	III	Aridis
MEDI4893/AR320	Hla	III	Medimmune
ASN100	Hla and LukGH	II	Arsanis
None	Hla	Primary screening	Trinomab Biotech

Antibody

Antigenic targets

Phase

Companies

AR-301/Salvecin

Hla

III

Aridis

MEDI4893/AR320

Hla

III

Medimmune

ASN100

Hla and LukGH

Arsanis

None

Hla

Primary screening

Trinomab Biotech

Compounds	Sources	Mechanism	References
Norwogonin	Scutellaria baicalensis	Targeting AgrA to inhibit Hla production	[20]
Cinnamaldehyde	Cinnamon essential oil	Acting as a β-lactam adjuvant, targeting SarA to suppress Hla via downregulation of mecA	[96]
Citral	Litsea cubeba essential oil	Interfering with the quorum sensing (QS) system to inhibit Hla expression	[97]
Schisandrone	Lignans	Inhibiting Hla expression	[98]
Isosakuranetin	Bergamot	Inhibiting the transcription and expression of Hla via regulation of upstream RNAIII	[99]
Ampelopsin	Ampelopsis grossedentata	Unclear	[100]
Flavone	Edible plants	Unclear	[101]
Echinatin	Licorice	Suppressing the Agr system, thereby inhibiting Hla expression	[102]
Bavachin	Psoralea corylifolia	Inhibiting Hla expression	[103]
7,8-dihydroxyflavone	Various foods	Inhibiting Hla expression	[104]
Hispidulin	Onopordum acanthium	Targeting the AgrAC system	[105]
10-hydroxy-2-decenoic acid (10-HDA)	Royal jelly	Unclear	[106]
Kaempferol	Various plants	Inhibiting Hla expression	[107]
2,3-dehydrokievitone	Lupine root	Inhibiting Hla expression	[108]
Andrographis paniculata lactone	Labdane diterpenoids isolated from the stems and leaves of Andrographis paniculata	Downregulating the transcription of the Hla gene and its highly associated genes (clfA and fnbA) to inhibit Hla expression	[109]
Luteolin	Various plants and foods	Downregulating the hla gene to inhibit Hla expression	[110]
Naringenin	Oak tree	Targeting AgrB to inhibit Hla secretion	[38]
Fisetin	Rhus succedanea	Targeting AgrB to inhibit Hla secretion	[38]
6-ES	Bocconia frutescens	Unclear	[111]
BiochaninA	Red clover, cabbage, and alfalfa	Inhibiting Hla expression	[112]
Epigallocatechin gallate	Green tea	Inhibiting Hla expression and heptamer pore formation	[113]
Lycopene	Tomato	Inhibiting Hla expression	[114]
Myricetin	Vegetables and fruits	Inhibiting Hla expression	[115]
Pilocarpine	Peganum harmala seeds	Inhibiting Hla expression	[116]
Piperine	Black pepper	Inhibiting Hla expression	[117]
Scutellarin	Herbal medicines	Targeting caseinolytic protease P (ClpP) to inhibit Hla	[118]
Emodin	Polygonum cuspidatum	Unclear	[119]
Brazilin	Dried heartwood of Caesalpinia sappan	Targeting SaeR to inhibit Hla	[21]
Isoliquiritigenin	Licorice	Inhibiting Hla expression	[120]

Compounds

Sources

Structure

Mechanism

References

Norwogonin

Scutellaria baicalensis

Targeting AgrA to inhibit Hla production

[20]

Cinnamaldehyde

Cinnamon essential oil

Acting as a β-lactam adjuvant, targeting SarA to suppress Hla via downregulation of mecA

[96]

Citral

Litsea cubeba essential oil

Interfering with the quorum sensing (QS) system to inhibit Hla expression

[97]

Schisandrone

Lignans

Inhibiting Hla expression

[98]

Isosakuranetin

Bergamot

Inhibiting the transcription and expression of Hla via regulation of upstream RNAIII

[99]

Ampelopsin

Ampelopsis grossedentata

Unclear

[100]

Flavone

Edible plants

Unclear

[101]

Echinatin

Licorice

Suppressing the Agr system, thereby inhibiting Hla expression

[102]

Bavachin

Psoralea corylifolia

Inhibiting Hla expression

[103]

7,8-dihydroxyflavone

Various foods

Inhibiting Hla expression

[104]

Hispidulin

Onopordum acanthium

Targeting the AgrAC system

[105]

10-hydroxy-2-decenoic acid (10-HDA)

Royal jelly

Unclear

[106]

Kaempferol

Various plants

Inhibiting Hla expression

[107]

2,3-dehydrokievitone

Lupine root

Inhibiting Hla expression

[108]

Andrographis paniculata lactone

Labdane diterpenoids isolated from the stems and leaves of Andrographis paniculata

Downregulating the transcription of the Hla gene and its highly associated genes (clfA and fnbA) to inhibit Hla expression

[109]

Luteolin

Various plants and foods

Downregulating the hla gene to inhibit Hla expression

[110]

Naringenin

Oak tree

Targeting AgrB to inhibit Hla secretion

[38]

Fisetin

Rhus succedanea

Targeting AgrB to inhibit Hla secretion

[38]

6-ES

Bocconia frutescens

Unclear

[111]

BiochaninA

Red clover, cabbage, and alfalfa

Inhibiting Hla expression

[112]

Epigallocatechin gallate

Green tea

Inhibiting Hla expression and heptamer pore formation

[113]

Lycopene

Tomato

Inhibiting Hla expression

[114]

Myricetin

Vegetables and fruits

Inhibiting Hla expression

[115]

Pilocarpine

Peganum harmala seeds

Inhibiting Hla expression

[116]

Piperine

Black pepper

Inhibiting Hla expression

[117]

Scutellarin

Herbal medicines

Targeting caseinolytic protease P (ClpP) to inhibit Hla

[118]

Emodin

Polygonum cuspidatum

Unclear

[119]

Brazilin

Dried heartwood of Caesalpinia sappan

Targeting SaeR to inhibit Hla

[21]

Isoliquiritigenin

Licorice

Inhibiting Hla expression

[120]