非抗生素类活性物质抗幽门螺杆菌研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2022-0089

摘要/Abstract

摘要：

幽门螺杆菌感染与多种胃部相关疾病（如胃溃疡、胃癌等）密切相关,是一种严重威胁人类健康的全球性流行病。过去临床上主要通过三联或四联疗法治疗幽门螺杆菌感染,然而由于抗生素的长期使用,幽门螺杆菌不断产生耐药性,导致临床治愈率逐年下降。针对这一问题,近年来非抗生素类抗菌活性物质由于不易诱导耐药性而逐渐受研究者更多关注。本文综述了非抗生素类活性物质（包括植物天然产物、糖脂、多不饱和脂肪酸、抗菌肽、尿素代谢抑制剂和益生菌）在抗幽门螺杆菌感染领域的研究概况和进展,重点介绍了不同活性物质的抗菌机制（如破坏细胞膜、抗生物膜、抑制幽门螺杆菌脲酶、竞争性抑制细菌粘附和分泌细菌素等）和对宿主机体的影响（如抗炎、抑制凋亡、促进黏膜和溃疡的修复及调节消化道菌群等）,同时还比较了它们在临床上应用途径的差异。最后,提出了该领域未来需要解决的关键问题,以期为这类物质开发为药物并用于临床提供理论依据与参考。

关键词: 幽门螺杆菌, 耐药性, 非抗生素活性物质, 天然产物, 抗菌活性

Abstract:

Helicobacter pylori infection is closely related to multiple gastric diseases,it is global epidemics threatening human health. In past few decades,the main treatment of H. pylori infection were combination of a variety of antibiotics. However,due to long-term abuse of antibiotics and nature defects of threatment,H. pylori obtained resistance to clinical drugs,leading to the clinical cure rate declined steadly. In response to this issue,non-antibiotics antibacterial active substances gained more attention from researchers in recent years because it induce less drug resistance. This review summarizes the updated status and progress of non-antibiotic substances（includes natural product from plant,glycolipids,polyunsaturated fatty acids,antimicrobial peptide,urease metabolism inhibitor and probiotics）against H. pylori infection,while focusing on the antibacterial mechanism（such as lysing membrane,anti-biofilm,inhibiting H. pylori urease,competitively inhibiting adhesion and secreting bacteriocin）and effect of host body（such as anti-inflammation,inhibiting cell apoptosis,promoting the repair of mucosa and uclers,and regulating digestive canal flora）. At the same time,the differences of their clinical application approaches of different active substances. Finally,the current key challenges are also included,aiming to provides theoretic foundation and reference for the development of such substances as clinical drugs.

Key words: Helicobacter pylori, drug resistance, non-antibiotic active substance, nature product, antibacterial activity

刘晓黎, 童真艺, 赵亮, 尹丽, 刘晨光. 非抗生素类活性物质抗幽门螺杆菌研究进展[J]. 生物技术通报, 2022, 38(9): 96-105.

LIU Xiao-li, TONG Zhen-yi, ZHAO Liang, YIN Li, LIU Chen-guang. Research Progress in Non-antibiotic Active Substances Against Helicobacter pylori[J]. Biotechnology Bulletin, 2022, 38(9): 96-105.

图/表 5

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化合物类型 Compound type	活性成分 Ingredients	作用机制 Mechanism	参考文献 Reference
有机硫Organic sulfur	大蒜素Allicin	裂解细胞壁Lyze cell war	[15]
生物碱Alkaloid	小檗碱Berberine	抑制生物膜形成、抗炎Inhibit biofilm formation & anti-inflammatory	[17-18]
	原小檗碱家族Protoberberine group	抑制脲酶活性、促进溃疡修复Inhibit urease activity & promote ulcer recovery	[19-20，26]
有机酸Organic acid	鞣花酸Ellagic acid	抑制能量代谢、促进黏膜修复Inhibit energy metabolism and promote mucosa recovery	[27]
萜类Terpenoid	广藿香醇 Patchouli alcohol	抑制脲酶活性、抑制细菌外排泵基因表达Inhibit urease activity & inhibit efflux pump gene express	[28-29]
	广防风内酯Ovatodiolide	抗炎、抑制细菌蛋白表达Anti-inflammation and inhibit protein express	[30]
类黄酮Flavonoid	二氢丹参酮Dihydrotanshinone	抑制能量代谢、清除成熟生物膜 Inhibit energy metabolism & eradicate mature biofilm	[21]
	橙皮苷Hesperetin	下调细菌基因表达（脲酶、鞭毛及毒力因子）Down-regulate gene express（urease，flagella and virulence factors）	[22]
	杨梅素Myricetin	抑制细菌转型及生物膜形成 Inhibit cell transformation & biofilm formation	[23]

化合物类型 Compound type	活性成分 Ingredients	作用机制 Mechanism	参考文献 Reference
有机硫Organic sulfur	大蒜素Allicin	裂解细胞壁Lyze cell war	[15]
生物碱Alkaloid	小檗碱Berberine	抑制生物膜形成、抗炎Inhibit biofilm formation & anti-inflammatory	[17-18]
	原小檗碱家族Protoberberine group	抑制脲酶活性、促进溃疡修复Inhibit urease activity & promote ulcer recovery	[19-20，26]
有机酸Organic acid	鞣花酸Ellagic acid	抑制能量代谢、促进黏膜修复Inhibit energy metabolism and promote mucosa recovery	[27]
萜类Terpenoid	广藿香醇 Patchouli alcohol	抑制脲酶活性、抑制细菌外排泵基因表达Inhibit urease activity & inhibit efflux pump gene express	[28-29]
	广防风内酯Ovatodiolide	抗炎、抑制细菌蛋白表达Anti-inflammation and inhibit protein express	[30]
类黄酮Flavonoid	二氢丹参酮Dihydrotanshinone	抑制能量代谢、清除成熟生物膜 Inhibit energy metabolism & eradicate mature biofilm	[21]
	橙皮苷Hesperetin	下调细菌基因表达（脲酶、鞭毛及毒力因子）Down-regulate gene express（urease，flagella and virulence factors）	[22]
	杨梅素Myricetin	抑制细菌转型及生物膜形成 Inhibit cell transformation & biofilm formation	[23]

底物类型 Compound type	活性物质 Active content	合成模式 Synthesis method	参考文献 Reference
类黄酮 Flavonoid	紫草醌 Shikonin	半合成 Semi-synthesis	[55]
	绿原酸 Chlorogenic acid	半合成 Semi-synthesis	[57]
萜类 Terpenoid	香芹酮 Carvone	半合成 Semi-synthesis	[58]
尿素类似物 Urea analogue	硫脲 Thiourea	全合成 Total-synthesis	[56]
咔唑-三嗪 Carbazole-triazine	咔唑 Carbazole	全合成 Total-synthesis	[59]

底物类型 Compound type	活性物质 Active content	合成模式 Synthesis method	参考文献 Reference
类黄酮 Flavonoid	紫草醌 Shikonin	半合成 Semi-synthesis	[55]
	绿原酸 Chlorogenic acid	半合成 Semi-synthesis	[57]
萜类 Terpenoid	香芹酮 Carvone	半合成 Semi-synthesis	[58]
尿素类似物 Urea analogue	硫脲 Thiourea	全合成 Total-synthesis	[56]
咔唑-三嗪 Carbazole-triazine	咔唑 Carbazole	全合成 Total-synthesis	[59]

益生菌菌株 Probiotic strain	抗H. pylori机制 Anti-H. pylori mechanism	分子机制 Molecular mechanism	参考文献Reference
嗜热链球菌Streptococcus thermophilus CRL1190	降低炎症反应、抑制黏附Reduce inflammation & inhibit bacteria adhesion	分泌胞外多糖1190 Secrete extra-polysaccharides 1190	[70-71]
植物乳杆菌Lactiplantibacillus plantarum ATCC 14917T& R1012	抑制毒力因子分泌及脲酶活性Inhibit toxic factor secretion & urease activity	分泌有机酸和拮抗因子Secrete organic acids & antagonistic factor	[72]
鼠李糖乳杆菌Lactobacillus rhamnosus GMNL-74 & 嗜酸乳杆菌Lactobacillus acidophilus GMNL-185	抑制黏附及毒力因子分泌Inhibit adhesion & toxic factor secretion	降低血液中胆固醇水平Reduce cholesterol level in serum	[73]
干酪乳杆菌Lactobacillus casei DGDG & 嗜酸乳杆菌Lactobacillus acidophilus LA14	抑制脲酶活性、调节肠道菌群Inhibit urease activity & regulate intestinal flora	分泌乳酸等有机酸Secrete lactic acid and other organic acids	[74]
鼠李糖乳杆菌Lactobacillus rhamnosus JB3	抑制毒力因子分泌及鞭毛运动Inhibit toxic factor secretion & flagellar movement	降低宿主受体表达、分泌拮抗因子Reduce host receptor expression & secrete antagonistic factor	[75]