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Advances in Clinical Medicine
Vol. 13  No. 07 ( 2023 ), Article ID: 68324 , 6 pages
10.12677/ACM.2023.1371493

幽门螺杆菌耐药机制的研究进展

王坷娜1，张骏2*

1浙江中医药大学第二临床医学院，浙江 杭州

2浙江省人民医院消化内科，浙江 杭州

收稿日期：2023年6月3日；录用日期：2023年6月28日；发布日期：2023年7月5日

摘要

幽门螺杆菌(Helicobacter pylori, Hp)是一种微需氧的螺旋状革兰阴性杆菌，能引起多种胃肠道疾病。根除Hp可显著降低消化性溃疡的复发率和胃癌的发病风险，但由于抗生素的不合理应用等问题，Hp的耐药率日渐升高，给临床根除治疗带来极大困难。因此，本文就Hp耐药机制的研究现状和进展作一综述。

关键词

幽门螺杆菌，抗生素，耐药机制

Progress on Drug Resistance Mechanism of Helicobacter pylori

Kena Wang1, Jun Zhang2*

1The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou Zhejiang

2Department of Gastroenterology, Zhejiang Provincial People’s Hospital, Hangzhou Zhejiang

Received: Jun. 3rd, 2023; accepted: Jun. 28th, 2023; published: Jul. 5th, 2023

ABSTRACT

Helicobacter pylori (H. pylori) is a microaerobic, spiral-shaped, and Gram-negative bacterium that causes multiple gastrointestinal diseases. H. pylori eradication can significantly reduce peptic ulcer occurrence and recurrence, and the risk of gastric cancer. However, due to the unreasonable application of antibiotics and other problems, H. pylori antibiotic resistance rate is increasing, which brings great difficulties to clinical H. pylori eradication. Therefore, this article reviews the current status and progress in study of drug resistance mechanisms of H. pylori.

Keywords:Helicobacter pylori, Antibiotic, Resistance Mechanism

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

幽门螺杆菌(Helicobacter pylori, Hp)是一种生存于人体胃部的具有传染性的革兰氏阴性杆菌。迄今为止，全球约有44亿Hp感染患者，占世界人口的50%左右，甚至在发展中国家Hp发病率已高达80% [1] 。Hp作为I类致癌原与消化性溃疡、胃癌等消化系统疾病以及缺铁性贫血、特发性血小板减少性紫癜等胃肠外疾病密切相关 [2] [3] ，国内外指南均推荐Hp阳性患者接受根除治疗 [4] [5] 。目前，抗生素治疗一直是临床上根除Hp的主要方法，常用的抗生素主要有克拉霉素、甲硝唑、阿莫西林、左氧氟沙星、呋喃唑酮、四环素等。但由于抗生素的不合理应用等问题，Hp的耐药率正逐渐升高，特别是甲硝唑、克拉霉素和左氧氟沙星耐药率均处于较高水平，而阿莫西林耐药率虽低，但也呈逐年上升趋势 [6] [7] 。在我国大陆地区针对抗Hp耐药性分析发现甲硝唑、克拉霉素、左氧氟沙星与阿莫西林在2019~2020年达到或接近最高值，耐药率分别为85.2%、33.0%、41.6%与17.5% [6] 。因此，Hp的抗生素耐药性问题亟待解决，本文通过研究国内外相关文献，对Hp耐药机制的研究进展进行梳理。

2. 基因突变与抗菌药物

2.1. 导致Hp对克拉霉素耐药的突变

克拉霉素通过与细菌50S亚基结合，干扰细菌蛋白质的合成而发挥抗菌作用。事实上，早在1996年就有关于Hp对克拉霉素耐药的研究，该研究 [8] 提出Hp对克拉霉素产生耐药性是其核糖体50S中亚基23SrRNA的肽基转移酶环(V结构域)发生点突变的结果。所有Hp耐药菌株均有A2146G (以前称为A2142G)和A2147G (以前称为A2143G)，这些突变影响核糖体与药物相互作用的亲和力，从而不能抑制细菌蛋白质的合成 [9] 。但除了上述两个突变外，还有研究发现了一些新的突变，如A2115G、A2144T、G2141A和T2182C，这些新突变和经典突变之间的差异可能在于克拉霉素最低抑菌浓度(minimum inhibitory concentration, MIC)不同 [10] [11] 。此外，编码细菌核糖体蛋白L22的hp1314 (rpl22)基因和编码翻译起始因子IF-2的hp1048 (infB)基因的突变也与克拉霉素耐药有关，并与23SrRNA突变显示协同作用 [12] [13] 。另外，通过基因组学分析，有研究发现hp1181和hp1184基因突变可能是Hp对克拉霉素耐药产生的最早、最持久的反应，这项研究也可能有助于Hp耐药的早期诊断、预防和治疗 [14] 。

2.2. 导致Hp对甲硝唑和左氧氟沙星耐药的突变

甲硝唑通过还原反应产生亲电物质，能有效破坏细菌蛋白质和核酸从而杀死细菌，达到抗Hp的目的 [15] 。许多研究表明rdxA (编码对氧不敏感的NADPH硝基还原酶)、frxA (编码NADPH黄素氧化还原酶)和fdxB (编码铁氧还原蛋白类似物)基因的突变与不同水平的甲硝唑耐药有关，但是单一的fdxB基因突变只导致Hp对甲硝唑的低水平耐药甚至不耐药，而rdxA和frxA突变则与高水平的甲硝唑耐药有关 [16] [17] [18] 。另有研究提出在rdxA突变中似乎只有R16H/C和M21A位点与甲硝唑耐药相关 [19] 。但是Hp对甲硝唑产生耐药作用似乎不能用单一机制来解释，有研究 [13] 发现在MIC值最高的菌株中除全长rdxA错义突变外，还存在dppA基因和dapF基因的突变，但这项研究的样本数量可能比较有限，未来仍需加大实验样本，明确上述突变位点与甲硝唑耐药的相关性。

左氧氟沙星作为根除Hp感染的常用治疗药物之一，是一种氟喹诺酮类抗生素，以细菌的脱氧核糖核酸(DNA)为靶，妨碍DNA旋转酶(拓扑异构酶II)和拓扑异构酶IV，进一步造成细菌DNA的不可逆损害，达到抗菌效果 [20] 。其中DNA旋转酶，由2个gyrA和2个gyrB亚基组成，是维持DNA螺旋结构所必需的酶 [20] 。Hp对左氧氟沙星耐药主要是与gyrA基因内喹诺酮类药物耐药决定区的Asn-87和(或)Asp-91点突变有关，同样gyrB基因突变也可以在耐药中发挥作用，但这些突变通常与gyrA基因突变共存 [19] [21] 。此外，近期也有研究发现并证实gyrA基因内新的Gly-85点突变与氟喹诺酮类耐药相关 [22] 。在此研究中分析了2006株耐药菌株，其中，15株在gyrA中表现出Asn-87突变(51.7%)，12株在Asp-91 (41.4%)出现突变，并且发现了之前从未报道过的Gly-85点突变 [22] 。

2.3. 导致Hp对阿莫西林耐药的突变

阿莫西林作为治疗Hp的四联方案中常用抗生素之一，同其他β-内酰胺类抗生素一样，能抑制胞壁粘肽合成酶，即青霉素结合蛋白(PBPs)，从而阻碍细胞壁粘肽合成，使细菌胞壁缺损，菌体膨胀裂解 [23] 。不少学者认为PBPs突变是引起阿莫西林耐药的根本原因，编码PBPs的pbp1A的基因突变可能是Hp对阿莫西林耐药的主要原因 [24] [25] 。同时，有研究 [26] 分析表明，除了pbp1A的基因突变外，其他分子机制还可能导致Hp对阿莫西林耐药，例如其他蛋白质PBP2、PBP3和PBP4的变化等。

3. 外排泵与生物膜

3.1. 外排泵的表达

外排泵是由一系列转运体组成，革兰氏阴性菌表达大量外排泵，可以将具有不同结构(包括抗生素)的分子转运出细胞，这种外排降低了细胞中抗生素的浓度，并使细菌能够在更高的抗生素浓度下存活 [27] 。因此，外排泵的过表达可导致Hp的临床相关耐药性。研究发现，外排泵介导了Hp对阿莫西林、甲硝唑和克拉霉素的耐药性 [28] [29] [30] 。研究 [28] 指出，影响药物外排的转运蛋白HP0939、HP0497和HP0471同时参与了Hp多药耐药和生物膜形成。敲除转运蛋白HP0939、HP0497和HP0471后不仅增加了Hp对多种抗生素的敏感性，并在体外抑制了完整生物膜的形成 [28] 。另外，在具有生物膜的细菌中，外排基因的表达也显著增加 [31] [32] 。因此，外排泵与生物膜可以通过协同作用以增加耐药性。

3.2. 生物膜

Hp具有在体内和体外形成生物膜的能力，生物膜在体外可增加Hp对克拉霉素、阿莫西林和甲硝唑的耐药 [32] 。细胞外聚合物(EPS)在Hp生物膜耐药性中起重要作用。EPS位于生物膜的最外层，可以为生物膜内的细胞提供保护，避免了人体免疫细胞与细菌的直接相互作用并减少了抗生素的渗透 [33] 。近年来，外膜蛋白在致病性和耐药性中的作用也是主要研究热点。Hathroubi等人发现，生物膜形成导致的耐药性部分取决于外膜蛋白的变化，并且通过增加细胞外蛋白酶K的水平可以降低克拉霉素耐药性 [34] 。

4. 毒力因子分泌

近年来，一些研究 [35] [36] 提出毒力因子与Hp耐药性之间是有关联的，但该结论目前尚存在争议。其中有研究 [35] 提出甲硝唑耐药性与细胞毒素相关基因A (cagA)和空泡细胞毒素基因A (vacA)的基因型有关。在耐药菌株中，vacA s1m1/cagA+型最常见，其次是vacA s1m1/cagA−型 [35] 。另有研究 [36] 指出cagA+菌株会显著增加Hp对甲硝唑耐药的风险。此外，vacA s1m1不仅显著增加了对甲硝唑的耐药性，也增加了对阿莫西林和左氧氟沙星的耐药性，而vacA s1m2则降低了对克拉霉素和甲硝唑的耐药性 [36] 。但是同时有研究提出毒力因子与耐药性或易感性之间没有显著关联 [37] 。因此，Hp毒力因子和耐药性之间的关系及作用机制仍需进一步研究阐明。

5. 结论

近年来，Hp对多种抗菌药物的耐药性迅速增加，尤其对克拉霉素、甲硝唑、左氧氟沙星和阿莫西林的耐药率更是逐年递增。Hp可以迅速适应变化的环境，并通过多种耐药机制(基因突变、外排泵、生物膜形成、毒力因子)抑制抗生素的活性。因此，全面了解Hp的耐药机制，有助于临床医师实施个体化的治疗策略，优化根除疗法，尽量选择敏感抗生素的根除方案，减少耐药菌株的形成与播散，避免抗生素的滥用，从而提高Hp根除率。

文章引用

王坷娜,张 骏. 幽门螺杆菌耐药机制的研究进展
Progress on Drug Resistance Mechanism of Helicobacter pylori[J]. 临床医学进展, 2023, 13(07): 10694-10699. https://doi.org/10.12677/ACM.2023.1371493

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    38. NOTES

    *通讯作者。

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