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噬菌体内溶素的应用及其作用机制的研究进展

韩泽华 杨小燕 李莲 陈昱良 杨爱 李雪林 向盈盈

韩泽华, 杨小燕, 李莲, 陈昱良, 杨爱, 李雪林, 向盈盈. 噬菌体内溶素的应用及其作用机制的研究进展[J]. 昆明医科大学学报.
引用本文: 韩泽华, 杨小燕, 李莲, 陈昱良, 杨爱, 李雪林, 向盈盈. 噬菌体内溶素的应用及其作用机制的研究进展[J]. 昆明医科大学学报.
Zehua HAN, Xiaoyan YANG, Lian LI, Yuliang CHEN, Ai YANG, Xuelin LI, Yingying XIANG. Application and Mechanism of Endolysins in Bacteriophages[J]. Journal of Kunming Medical University.
Citation: Zehua HAN, Xiaoyan YANG, Lian LI, Yuliang CHEN, Ai YANG, Xuelin LI, Yingying XIANG. Application and Mechanism of Endolysins in Bacteriophages[J]. Journal of Kunming Medical University.

噬菌体内溶素的应用及其作用机制的研究进展

基金项目: 国家自然科学基金(82360189);云南省科技厅基础研究专项基金(202301AT070483);云南省科技厅-昆明医科大学应用基础研究联合专项基金(202301AY070001-105);云南省高层次卫生健康技术人才培养专项基金(D2024005)
详细信息
    作者简介:

    韩泽华(1999~),男,白族,云南大理人,在读硕士研究生,主要从事口腔临床工作

    通讯作者:

    向盈盈,E-mail:25591394@qq.com

  • 中图分类号: R37

Application and Mechanism of Endolysins in Bacteriophages

More Information
    Corresponding author: 向盈盈,博士,昆明医科大学附属延安医院口腔科行政副主任、支部副书记,主任医师,昆明医科大学教授,硕士研究生导师。长期从事3D数字化精准口腔种植技术、CAD/CAM制作全瓷冠、嵌体及各类牙体缺损、牙列缺损、牙列缺失等疑难复杂病例治疗,开展噬菌体疗法在口腔临床医学中的应用研究。担任云南省口腔医学会生物医学专委会副主任委员,云南省口腔医学会修复专委会常务委员,云南女医师协会口腔分会常务委员、秘书,中国医药教育协会肿瘤内照射专委会委员,中华口腔医学会全科口腔医学专委会青年委员,中华口腔医学会口腔修复学专委会青年委员,云南省医师协会《口腔医师分会》委员,云南省高层次卫生健康技术人才医学学科带头人,昆明市春城计划青年拔尖人才,昆明市卫生科技人才培养百工程带头人,专家工作站2个,开展新技术8项。主持1项国家自然科学基金,3项省级项目,获云南省科技进步奖三等奖1项,云南省卫生科技成果奖三等奖4项,获授权发明专利6项、实用新型专利24项。以第一作者及通讯作者发表学术论文25篇,其中SCI论文11篇,在Microbial Pathogenesis发表系列文章3篇,组织工程TOP期刊发表论文1篇,是国际上首次系统地开展难治性根尖周炎噬菌体治疗的应用研究。
  • 摘要: 细菌耐药性的持续蔓延已成为全球公共卫生领域的重大挑战。噬菌体衍生的内溶素因其独特的抗菌机制,逐渐成为传统抗生素的潜在替代策略。内溶素是噬菌体编码的肽聚糖水解酶,通过裂解细菌细胞壁发挥杀菌作用,具有宿主特异性强、不易耐药、菌群干扰小及多靶点协同等优势。内溶素在人类医学、兽医学及食品工业等领域中对多种耐药菌表现出强效裂解活性。内溶素与传统抗生素联合应用可产生协同效应,显著降低抗生素的最低抑菌浓度,并提高感染模型的生存率。对内溶素作为新型抗菌剂的应用及作用机制进展进行综述,以期为后续将噬菌体内溶素应用于细菌耐药性感染的研究提供参考。
  • 图  1  噬菌体内溶素的模块化结构及其多样性

    A:具有一个N端EAD和一个C端CBD的模型;B:具有一个N端EAD和两个C端CBD的多域模型;C:具有一个C端EAD和一个N端CBD的模型;D:无CBD的EAD简单球形模型;E:CBD位于两个EAD之间的多域模型;F:除一个N端EAD和两个C端CBD外,还含有一个孢子结合结构域SBD。

    Figure  1.  Modular structure of phage endolysins and their diversity

    图  2  细菌细胞壁肽聚糖结构及内溶素作用位点示意图

    注:糖苷酶(Glycosidases):水解MurNAc-GlcNAc间的β-1,4键;酰胺酶(Amidases):水解MurNAc乳酸基与L-Ala间的酰胺键;内肽酶(Endopeptidases):水解肽桥或肽侧链内部肽键。

    Figure  2.  Bacterial cell wall peptidoglycan structure and endotoxin action sites

    图  3  噬菌体裂解革兰氏阴性菌的两条途径示意图

    A:“Holin-Endolysin”机制:穿孔素在内膜形成大孔道,内溶素借此进入周质空间降解肽聚糖,最终由斯潘素介导外膜破裂;B:“Pinholin-SAR endolysin”机制:微孔蛋白引发膜去极化,使锚定于内膜的非活性内溶素释放并活化,降解肽聚糖后同样由斯潘素完成裂解。

    Figure  3.  Two pathways by which bacteriophages lyse Gram-negative bacteria

    表  1  抗生素、噬菌体和内溶素抗菌特性对比

    Table  1.   Comparison of antibacterial properties of antibiotics,bacteriophages,and endolysins

    特性维度 抗生素 噬菌体 内溶素 参考文献
    杀菌特异性 广谱/窄谱,易扰乱微生态 种/株特异性极强,精准靶向致病菌 相对广谱的溶菌活性,可作用于多种口腔革兰氏阳性/阴性菌 [1415]
    增殖特性 非增殖,浓度依赖 在宿主菌内自我增殖,理论上单次给药可放大效应 非增殖,作用剂量可精确控制 [1617]
    作用方式 干扰细菌关键代谢(如细胞壁合成、蛋白合成) 劫持宿主菌代谢系统,破坏多个核心生物学过程 胞外酶解作用,靶向水解肽聚糖中特定化学键 [1518]
    杀菌速度 起效较慢,需数小时至数天 依赖感染周期,裂解释放耗时长 快速裂解,接触后数秒至数分钟内即发挥杀菌效应 [1920]
    胞内活性 部分可穿透宿主细胞膜,治疗胞内菌感染 无法穿透真核细胞膜,对胞内菌无效 天然活性有限,但经融合细胞穿透肽等改造后可增强胞内递送 [202165]
    耐药性风险 广泛存在且日益严重 细菌可通过受体突变等机制产生抗噬菌体性 至今未见临床耐药报道,可有效应对多重耐药菌株 [2223]
    抗生物被膜能力 渗透受限,对成熟生物膜效果差 渗透能力有限,难以清除生物膜深层细菌 可穿透生物膜基质,直接裂解其中细菌,破坏生物膜结构 [1537]
    免疫原性 多数无免疫原性 可被机体免疫系统识别并产生中和抗体 免疫原性较低,抗体中和作用较弱 [245964]
    药代动力学 体内过程明确,浓度-效应关系清晰 体内行为复杂,临床证据有限 可定量测定感染部位及血药浓度 [222360]
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