中药及活性成分抗耐药菌作用及其机制研究进展

doi:10.11843/j.issn.0366-6964.2025.04.014

摘要/Abstract

摘要：

细菌对抗菌药的耐药性可导致感染性疾病治疗难度增加、医疗负担加重及死亡率升高等问题，对全球人类和动物健康造成威胁，目前形势已十分严峻。在减抗禁抗的背景下，开发新的抗菌药或替代品以及抗菌药佐剂已刻不容缓。中药及活性成分在协同抗菌药控制细菌耐药性方面已展示出明显优势，具有广阔的开发应用前景。本文对2017年我国禁止硫酸黏菌素用作促生长剂(中华人民共和国农业部公告第2428号)以来，关于控制耐药菌的中药及活性成分以及其对耐药质粒、外排泵、细胞膜通透性、耐药酶、耐药基因、生物被膜等的作用等的最新研究进展进行综述，以期为开发对耐药菌有效的新抗菌药或抗菌增效剂提供参考。

关键词: 中草药, 中药活性成分, 抗菌药耐药性, 作用机制

Abstract:

Antimicrobial resistance can increase difficult in treatment of infectious diseases, medical burden and mortality, posing a threat to global human and animal health. In the background of reducing and banning antimicrobials, it is urgent to develop new antimicrobials, alternatives, as well as antimicrobials adjuvants. It has been demonstrated that Traditional Chinese medicine and its active components have significant advantages in controlling of antimicrobial resistance in combination with antimicrobials and has broad prospects for development and application. In this study, we reviewed the latest research progress on traditional Chinese medicine and its active components for controlling antimicrobial-resistant bacteria through acting on drug-resistant plasmids, efflux pumps, cell membrane permeability, drug-resistant enzymes, drug-resistant genes and biofilms since 2017 when China banned the use of colistin as a growth promoter (Announcement No. 2428 of the Ministry of Agriculture of China), to provide reference for the development of effective new antimicrobials or their synergist against antimicrobial-resistant bacteria.

Key words: Traditional Chinese Medicine, active ingredients of traditional Chinese medicine, antimicrobial resistance, mechanism

中图分类号:

S853.74

吴俊杰, 吕世明, 龙小霞, 王忠, 王立琦. 中药及活性成分抗耐药菌作用及其机制研究进展[J]. 畜牧兽医学报, 2025, 56(4): 1632-1647.

WU Junjie, Lü Shiming, LONG Xiaoxia, WANG Zhong, WANG Liqi. Research Progress on the Antibacterial Effects and Mechanisms of Traditional Chinese Medicine and Active Ingredients against Drug-resistant Bacteria[J]. Acta Veterinaria et Zootechnica Sinica, 2025, 56(4): 1632-1647.

图/表 6

表 1

以耐药菌质粒为靶点的中药及活性成分"

序号 No.	中药 TCM	耐药菌或动物 Drug resistant bacteria or animals	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	黄连素	耐碳青霉烯类肺炎克雷伯菌	黄连素MIC为(1.38±0.72) mg·mL^-1；作用24、48、72 h的质粒消除率分别为0, 3.1% 和4.7%	消除R质粒	李永伟等^[23]
2	金银花水煎剂	耐碳青霉烯类药物产金属酶铜绿假单胞菌7珠	金银花MIC为321.4 mg·mL^-1；作用24、48、72 h的质粒消除率分别为0、0.71% 和0.62%	消除R质粒	刘心伟等^[24]
3	黄岑苷、姜黄素、小檗碱、芦荟大黄素	携带多重耐药基因cfr的Incx4型质粒psD11的大肠杆菌	小檗碱、黄岑苷、芦荟大黄素MIC均为1 280 mg·mL^-1，姜黄素MIC＞160 mg·mL^-1；1/2、1/4MIC小檗碱和黄岑苷质粒消除率分别为25.46%、23.15%和14.66%、12.75%；1/2MIC的小檗碱和黄岑苷处理组的质粒稳定性下降率分别达49.33%和51.28%	消除Incx4型耐药质粒，影响其遗传稳定性，破坏细胞膜和细胞壁	陈璐等^[25]
4	苜蓿油(乙醚提取)	耐万古霉素的屎肠球菌	苜蓿油MIC为32~64 μg·mL^-1	抑制vanA/B基因和携带Tn1546转座子的质粒的接合转移	Ahmad等^[26]
5	双氢青蒿素(DHA)	携带pIncI2-mcr-1质粒、pIncX4-mcr-1质粒、bla_NDM-₅-IncX3质粒、pIncX3-bla _NDM-₅和tet(X4)-IncX1质粒的大肠杆菌，小鼠	对携带pIncI2-mcr-1、pIncX4-mcr-1质粒的MIC为4 μg·mL^-1；10和200 μg·mL^-1的DHA使pIncI2-mcr-1的接合转移频率分别降低4倍和180倍；同时使pInX4-mcr-1的接合转移频率分别降低6倍和160倍；200 μg·mL^-1的DHA使pIncX3-bla _NDM-5的接合转移频率降低2.7倍；使小鼠体内pIncI2-mcr-1的接合转移频率降低1倍	使ΔpH下降，ΔΨ增加，破坏质子动力，降低ATP含量；抑制接合转移相关基因的表达；从而抑制pIncI2-mcr-1质粒的接合转移	Wang等^[27]

表 1

表 2

作用于耐药菌外排系统的中药及活性成分"

序号 No.	中药 TCM	耐药菌 Drug resistant bacteria	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	黄岑苷	对磷霉素钠、氯霉素、头孢噻肟钠耐药大肠杆菌E320	黄岑苷和以下几种抗生素联合使用MIC由2.5 g·L^-1分别下降到0.625、0.625、0.313 g·L^-1，磷霉素钠由512 mg·L^-1降为64 mg·L^-1，氯霉素MICs由512 mg·L^-1降为128 mg·L^-1，头孢噻肟钠MIC由1 024 mg·L^-1降为256 mg·L^-1	抑制细菌主动外排系统、使AcrB蛋白表达降低	赵子玉等^[32]
2	黄岑苷	对阿奇霉素耐药的腐生葡萄球菌	黄芩苷MIC为500 mg·L^-1，阿奇霉素MIC为1 000 mg·mL^-1，黄岑苷与阿奇霉素呈协同作用	抑制外排系统来抑制细胞膜的形成及agr群体感应系统	Wang等^[33]
3	(浸渍法提取)和精油(EO)(蒸馏法提取)	耐甲氧西林药物金黄色葡萄球菌	CE的MIC为78~1 250 μg·mL^-1，EO的MIC为0.098%~0.195%	抑制细菌主动外排系统、降低外排泵基因norA和mepA的表达	Oo等^[34]
4	苦参碱	耐替加环素的肺炎克伯雷菌	苦参碱与替加环素联用后，苦参碱MIC由(3 181.82±1 139.61) mg·L^-1降为(1 221.59±618.83) mg·L^-1，替加环素MIC由(38.18±21.76) mg·L^-1(耐药)降为2.00 mg·L^-1(敏感)	使ramA、maeA、acrB基因表达量升高、acrR基因表达量降低从而抑制细菌主动外排系统	伍慧妍等^[35]
5	黄连素	对喹诺酮类、碳青霉烯类、氨基糖苷类、β-内酰胺类耐药鲍曼不动杆菌	黄连素MIC为256 μg·mL^-1，与黄连素联用后头孢他定、亚胺培南的MIC分别由64~128 mg·mL^-1降为32~64 mg·mL^-1和8~16 mg·mL^-1，氨曲南MIC由256~512 μg·mL^-1降为32~64 μg·mL^-1，环丙沙星MIC由8~16 μg·mL^-1降为4~8 μg·mL^-1	抑制细菌主动外排系统，消除mdfA质子泵	林少华等^[36]
6	水飞蓟宾	耐甲氧西林金黄色葡萄球菌	与水飞蓟宾联用环丙沙星和苯扎氯氨的MIC分别由128和4 μg·mL^-1降为32和2 μg·mL^-1	抑制细菌norA和qacA/B基因的表达、抑制外排系统	Wang等^[37]
7	木犀草素	msrA阳性化脓隐秘菌	木犀草素MIC为78~156 μg·mL^-1，木犀草素处理后大环内酯类药物对化脓隐秘菌的MIC显著降低	抑制msrA的表达，阻断MsrA外排泵的能量获取	Guo等^[38]
8	黄岑素	耐多西环素的鲍曼不动杆菌	黄岑素与1/4MIC多西环素联用FICI≤0.5，黄连素MIC为250 μg·mL^-1，与多西环素联用后使多西环素MIC由128 μg·mL^-1降为8 μg·mL^-1	破坏生物膜和抑制多药外排泵	Wang等^[40]
9	香芹酚和百里酚	携带NorA的野生型和NorA过表达金黄色葡萄球菌	与香芹酚和百里酚联用后诺氟沙星对野生型和NorA过表达金黄色葡萄球菌MIC由64和128 μg·mL^-1降为32和64 μg·mL^-1	与NorA结合从而抑制NorA的外排作用	Dos Santos等^[39]

表 2

表 3

作用于耐药酶的中药及活性成分"

序号 No.	中药 TCM	耐药菌 Drug resistant bacteria	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	黄柏、金银花、苦参、荆芥、荔枝草、白矾、玄明粉、川椒复方水煎剂	耐头孢曲松(CRO)、头孢噻肟(CTX)、头孢吡肟(FEP)的产ESBLs大肠杆菌	黄金洗剂MIC为0.6 g·mL^-1，0.5 g·mL^-1黄金洗剂的耐药消除率为FEP(13.9±1.3)%、CTX(2.9±1.1)%、CRO(3.0±1.6)%，0.1 g·mL^-1黄金洗剂的耐药消除率为FEP(5.6±3.5)%、CTX(1.9±1.2)%、CRO(2.1±1.2)%	抑制生物膜的形成和抑制超广谱β-内酰胺酶(ESBLs)的活性	衡雪源等^[44]
2	加味黄连解毒汤	产超广谱β内酰胺酶的大肠埃希菌	加味黄连解毒汤MIC 0.8 g·mL^-1	抑制ESBLs活性和含量	Li等^[45]
3	芸香苷	大肠杆菌E320、CTX-M-14阳性菌BL-21	与头孢噻肟钠联合使用(FICI=0.236和0.375)，芸香苷单独使用MIC均为2.5 mg·mL^-1，头孢噻肟钠单独使用对E320的MIC为1 024 μg·mL^-1对CTX-M-14阳性菌MIC为＞1 024 μg·mL^-1	抑制β-内酰胺酶活性	赵子玉等^[46]
4	厚朴酚	NDM-1阳性大肠杆菌	与厚朴酚联用后美罗培南MIC由16~64 μg·mL^-1降为4~16 μg·mL^-1	抑制NDM-1酶活性(IC₅₀=6.47 μg·mL^-1)	Liu等^[47]
5	紫檀芪	NDM-1阳性大肠杆菌和肺炎克雷伯菌	与紫檀芪联用后美罗培南MIC由16~128 μg·mL^-1降为4~32 μg·mL^-1，全身感染耐药菌的小鼠存活率升高52%	抑制NDM-1酶活性(与Trp93和Asp124的残基结合)	Liu等^[48]
6	漆黄素	NDM-1阳性大肠杆菌	与漆黄素联用后美罗培南MIC由16~37.33 μg·mL^-1降为4~5.33 μg·mL^-1，全身感染耐药菌的小鼠存活率升高40%	抑制NDM-1酶活性(与Val73，Met248或His250结合，IC₅₀=9.68 μg·mL^-1)	Guo等^[49]
7	异甘草苷	NDM-1阳性大肠杆菌和肺炎克雷伯菌	与异甘草苷联用后美罗培南MIC由16~64 μg·mL^-1降为4~16 μg·mL^-1	抑制NDM-1酶活性	Wang等^[50]
8	茶黄素-3, 3′-二加酸酯	MRSA	与β内酰胺类抗生素联用FICI=0.313或0.188，β内酰胺类抗生素MICs由16~256 μg·mL^-1降为4~32 μg·mL^-1	抑制金属β内酰胺酶(MBLs)的水解活性(与Gln242和Ser369结合)	Teng等^[51]
9	广藿香酮	MCR-l阳性大肠埃希菌、肺炎克雷伯菌及鼠伤寒沙门菌	与黏菌素联合使用(FICI≤0.5)，广藿香酮MIC为512 μg·mL^-1，黏菌素MIC均＞8 μg·mL^-1	抑制MCR-1酶活性(直接占据氨基酸Ser330、Asp331和Phe344)	解胜男^[42]
10	蛇床子素	mcr-1阳性大肠杆菌和肺炎克雷伯菌	与黏菌素联用FIC=0.11±0.04 ~0.29±0.10，黏菌素的MIC由1~32 μg·mL^-1降为0.67~13.33 μg·mL^-1	抑制MCR-1酶活性	Zhou等^[52]
11	和厚朴酚	MCR-1阳性肺炎克雷伯菌和大肠杆菌	与多黏菌素B联用FICI=0.09±0.00~0.27±0.06多黏菌素B由MIC0.5~512 μg·mL^-1降为0.42~5.33 μg·mL^-1，全身感染耐药菌的小鼠存活率升高40%	抑制MCR-1酶活性(与残基Ser284、Tyr287和Pro481结合)	Guo等^[53]
12	异土木香内酯	mcr-1阳性肺炎克雷伯菌和大肠杆菌	与多黏菌素B联用FIC＜0.5，多黏菌素MIC由0.5~64 μg·mL^-1降为0.5~6 μg·mL^-1，全身感染耐药菌的小鼠存活率升高40%	抑制MCR-1酶活性	Lu等^[54]
13	木豆素芪酸	mcr-1阳性大肠杆菌	与多黏菌素B联用FICI=0.13~0.51，多黏菌素B的MIC由4~16 μg·mL^-1降为1~2 μg·mL^-1	抑制MCR-1酶活性	Jia等^[55]
14	棕榈碱	QnrS和AAC(6′)-Ib-cr阳性大肠杆菌	棕榈碱MIC为1 024~2 048 μg·mL^-1，与环丙沙星联合使用FIC=0.375~0.5，环丙沙星MICs由4~128 μg·mL^-1下降为2~16 μg·mL^-1	抑制QnrS的旋转酶保护作用和AAC(6′)-Ib-Ib-cr的乙酰化作用	Wang等^[56]

表 3

表 4

作用于耐药菌细胞膜的中药及活性成分"

序号 No.	中药 TCM	耐药菌 Drug resistant bacteria	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	平味丸	大肠杆菌ATCC、DH5α、ZJ478和肺炎克雷伯菌ZJ02、ZJ05以及沙门菌HYM2、ZZW20、15E464	平味丸MIC为1.024 mg·mL^-1，黏菌素MIC由(1.5±0.58)~(53.33±18.48)μg·mL^-1降为＜4 μg·mL^-1；平胃丸和黏菌素联用延长了沙门菌HYM2感染小鼠和鸡模型的中位生存期，降低了感染动物的细菌负荷和脏器指数，减轻了盲肠的病理损伤	加快破坏细胞膜的通透性	Sheng等^[57]
2	猴耳环乙酸乙酯提取物	MRSA	联用后红霉素、头孢曲松钠和左氧氟沙星的MIC₉₀分别由1 024、2 048和32 μg·mL^-1降为256、1 024和16 μg·mL^-1	破坏细胞膜的通透性以及抑制PBP2a的表达	Liu等^[58]
3	麝香草酚	mcr-1阳性肺炎克雷伯菌和大肠埃希菌	与黏菌素联用体内(P < 0.05)和体外(FICI < 0.5)，黏菌素耐药菌株的黏菌素MICs由4~1 024 mg·L^-1降为≤1 mg·L^-1	抑制细胞膜形成、破坏生物膜的完整性	Yao等^[59]
4	槲皮素	对黏菌素耐药的鲍曼不动杆菌	槲皮素与黏菌素联用FICI=0.187 5~0.5, 与阿米卡星联用FICI=0.187 5~0.282 5, 与黏菌素联用MIC由128~256 μg·mL^-1降低到8~32 μg·mL^-1, 与阿米卡星联用MIC降低到32~64 μg·mL^-1	破环细胞膜的完整性	Odabas等^[60]
5	石菖蒲根茎己烷提取物(Acorus calamus L. rhizome hexane AC-R-H)及其生物活性组分(S-III-BAF)	耐多药大肠杆菌、铜绿假单胞菌、鲍曼不动杆菌、蜡样芽胞杆菌	AC-R-H与氨苄西林联用对蜡样芽胞杆菌(FICI=0.365)、铜绿假单胞菌(FICI=0.456)和鲍曼不动杆菌(FICI=0.245)，联用后氨苄西林对蜡样芽胞杆菌、大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌的MIC分别由10、100、15、12.5 mg·mL^-1下降为1.25、25、3.25、3.12 mg·mL^-1	破坏细胞膜的完整性，增强细胞膜的通透性	Kongkham等^[61]

表 4

表 5

作用于耐药基因的中药及活性成分"

序号 No.	中药 TCM	耐药菌 Drug resistant bacteria	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	丁香酚	黏菌素耐药大肠杆菌	与黏菌素联用FICI=0.375~0.625，丁香酚MIC由4~8 μg·mL^-1降为1~4 μg·mL^-1，黏菌素MIC由1~16 μg·mL^-1降为0.25~2 μg·mL^-1	下调mcr-1基因的表达、直接抑制MCR-1活性	Wang等^[12]
2	黄连素	耐多黏菌素兔源性大肠杆菌	黄连素MIC为1.25 mg·mL^-1，多黏菌素MIC为16 μg·mL^-1, 氯丙嗪MIC为68 μg·mL^-1，黄连素和氯丙嗪的耐药消除率分别为26.9%和5.6%	消减大肠杆菌耐药基因mcr-1	王新兴等^[64]
3	黄芩、芍药、黄连、鱼腥草、艾叶水煎剂	含aac(3)-Ⅱ的多重耐药阳性猪源大肠埃希菌	MIC分别为黄岑0.3 g·mL^-1、黄连0.2 g·mL^-1、艾叶0.6 g·mL^-1、赤芍0.5 g·mL^-1、鱼腥草0.8 g·mL^-1，黄岑、黄连、艾叶、赤芍、鱼腥草对acc(3)-Ⅱ基因消除率分别为95%、83%、89%、78%、5%	消除耐药基因	黄永志等^[65]
4	杨树花、地榆、地锦草、马齿苋两两组成复方水煎剂	耐氨苄西林、头孢他啶、庆大霉素、大观霉素、卡那霉素、恩诺沙星、氧氟沙星、环丙沙星、四环素、复方新诺明的大肠杆菌	杨树花+地榆62.5 mg·mL^-1、杨树花+马齿草250 mg·mL^-1、杨树花+地锦草62.5 mg·mL^-1、地榆+马齿草125 mg·mL^-1，中药对大肠杆菌耐药性平均消除率在10%以上	消除耐药基因aacC3-Ⅱ、aacC2、aph(3′)-Ⅱ	鲁孟佳^[66]、李志君等^[67]
5	苏木、诃子、秦皮、五味子和黄连水煎剂	对β-内酰胺类、磺胺类以及其他抗菌药均耐药的貂源性大肠杆菌	苏木MIC为62.5~125.00 mg·mL^-1，诃子、秦皮、五味子MIC为31.25~62.50 mg·mL^-1，黄连MIC为62.5~250.00 mg·mL^-1，中药对大肠杆菌耐药性消除率为2.8%~12.7%	消除2~3个耐药基因：五味子对aadA、sul1和tetB效果较好，黄连对sul3和bla_TEM1基因效果较好，而诃子对bla_OXA1和bla_CTX-M基因效果较好	王婧文等^[68]
6	杠板归乙醇提取物和槲皮素	耐氟苯尼考大肠杆菌肠杆菌菌株DF2、GL26、GP46	杠板归提取物MIC为2.48~9.64 g·L^-1、槲皮素MIC为1.56~6.62 g·L^-1，提取物使大肠杆菌floR基因表达量下降8.84%~15.21%	消除耐药基因floR基因	唐远江等^[69]

表 5

表 6

作用于生物被膜的中药及活性成分"

序号 No.	中药 TCM	耐药菌 Drug resistant bacteria	对耐药菌的作用 The effect on drug-resistant bacteria	作用机制 Mechanism of action	参考文献 References
1	芦荟大黄素	野生型幽门螺旋菌	与阿莫西林、克拉霉素、左氧氟沙星、甲硝唑、利福平、四环素等抗生素联用后MIC分别由2、4、2、8、32、16 μg·mL^-1降为0.5、0.5、1、2、1、4 μg·mL^-1	芦荟大黄素破坏幽门螺杆菌的生物膜并抑制omp6的表达	Zhao等^[73]
2	鹧鸪茶乙醇提取物	泰国双歧杆菌	使用75 μg·mL^-1的鹧鸪茶处理双歧杆菌，使得生物膜形成量分别降低77.65%和47.78%。对已经形成的生物膜破坏率分别为28.18%和70.87%	抑制生物膜的生成及破坏成熟的生物膜、干扰细菌群体感应系统	Xu等^[74]
3	牡丹荚水提取物(WE)、乙酸乙酯提取物(EA)、正丁醇提取物(NB)、石油醚提取物(PE)、正丁醇提取物(NB)，及EA的主要成分没食子酸(GA)没食子酸甲酯(MG)，1, 2, 3, 4, 6-O-五甲酰基-β-D-葡萄糖(PG)和槲皮素(QU)	MRSA ATCC43300和金黄色葡萄球菌ATCC29213	0.031 mg·mL^-1EA的对MRSA的生物膜抑制率达到80%，0.625 mg·mL^-1的WE可以抑制参与生物膜形成。0.025 mg·mL^-1 PG、0.0125 mg·mL^-1MG和0.025 mg·mL^-1 QU对生物膜活性抑制率分别为87.7%、72.0%和51.9%，PG与甲氧西林(FICI≤0.5)和青霉素(FICI≤0.5)联用对MRSA具有协同作用，MG与甲氧西林(FICI≤0.5)联用对MRSA具有协同作用	抑制生物膜活性、影响生物膜形成	Jin等^[75]
4	丁香酚	沙雷菌C6LB	32.3 mmol·L^-1的丁香酚使生物膜形成量减少99%、可以去除62%的生物膜生物质，4.03 mmol·L^-1的丁香酚使生物膜黏附活性降低40%、使生物膜活性降低20%	降低生物膜的黏附性，抑制生物膜的形成	Frikha等^[76]
5	银杏叶水提取物(WE)、乙酸乙酯提取物(EA)、正丁醇提取物(NB)、石油醚提取物(PE)、正丁醇提取物(NB)	MRSA、溶血性链球菌	EA和PE对MRSA的MIC分别为8和4 μg·mL^-1，3倍MIC浓度的EA和PE完全抑制MRSA和溶血性链球菌生物膜的形成	抑制细菌生物膜的形成	Wei等^[77]
6	青蒿素	白色念珠菌	2 560、1 280、640和320 μg·mL^-1的青蒿素对白色念珠菌的生物膜抑制率分别为91.2%、78.5%、50% 和40.2%	抑制生物膜的形成	Sumlu等^[78]
7	柚皮素	临床分离的耐黏菌素肺炎克雷伯菌、大肠杆菌和鲍曼不动杆菌各7株	柚皮素与黏菌素联用具有协同作用(FICI < 0.5)，联用显著抑制生物膜的形成(P < 0.05)，联合用药显著提高大蜡螟的存活率(P < 0.05)	抑制生物膜的形成、破坏细胞膜的完整性	Xu等^[79]

表 6

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