生物技术通报 ›› 2022, Vol. 38 ›› Issue (9): 4-16.doi: 10.13560/j.cnki.biotech.bull.1985.2022-0759
• 细菌耐药性专题(专题主编: 刘雅红 教授 孙坚 教授) • 上一篇 下一篇
收稿日期:
2022-06-22
出版日期:
2022-09-26
发布日期:
2022-10-11
作者简介:
刘成程,博士,副教授,研究方向:抗菌光动力疗法;E-mail: 基金资助:
LIU Cheng-cheng1(), HU Xiao-fang2, FENG You-jun3()
Received:
2022-06-22
Published:
2022-09-26
Online:
2022-10-11
摘要:
抗生素的过度使用以及滥用加速了细菌耐药性的产生及蔓延。细菌耐药性俨然已成为导致人类死亡的第三大原因,严重威胁了全球公共健康。因此,当下亟需加强细菌耐药的机制研究,并探索应对耐药性的新型防控策略。针对几类重要耐药细菌,本文就细菌耐药的主要生化机制:药物渗透障碍、药物作用靶位改变、药物失活以及主动外排进行了总结;并对其防控策略:抗菌肽疗法、免疫疗法、噬菌体疗法、抗菌光动力疗法、益生菌疗法、抗菌纳米颗粒技术、反义寡核苷酸和基因编辑技术、宿主导向疗法等进行了归纳。该综述致力于为细菌耐药性进行科普,并为耐药性的相关研究提供参考。
刘成程, 胡小芳, 冯友军. 细菌耐药:生化机制与应对策略[J]. 生物技术通报, 2022, 38(9): 4-16.
LIU Cheng-cheng, HU Xiao-fang, FENG You-jun. Antimicrobial Resistance:Biochemical Mechanisms and Countermeasures[J]. Biotechnology Bulletin, 2022, 38(9): 4-16.
抗生素Antibiotics | 作用机制Action mechanisms |
---|---|
β-内酰胺类抗生素β-Lactams | 抑制细菌细胞壁合成 |
糖肽类抗生素Glycopeptides | 抑制细菌细胞壁合成 |
脂肽类抗生素Lipopeptides | 改变细菌细胞膜通透性 |
多黏菌素类抗生素Polymyxins | 改变细菌细胞膜通透性 |
氨基糖苷类抗生素Aminoglycosides | 抑制细菌蛋白质合成(作用30S 核糖体亚基) |
四环素类抗生素Tetracyclines | 抑制细菌蛋白质合成(作用30S 核糖体亚基) |
氯霉素类抗生素Chloramphenicol | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
林可酰胺类抗生素Lincosamides | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
大环内酯类抗生素Macrolides | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
恶唑烷酮类抗生素Oxazolidinones | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
链阳菌素类抗生素Streptogramins | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
喹诺酮类抗生素Quinolones | 抑制细菌核酸合成 |
磺胺类抗生素Sulfonamides | 抑制细菌代谢途径 |
甲氧苄啶Trimethoprim | 抑制细菌代谢途径 |
表1 抗生素的杀菌作用机制
Table 1 Action mechanisms of antibiotics
抗生素Antibiotics | 作用机制Action mechanisms |
---|---|
β-内酰胺类抗生素β-Lactams | 抑制细菌细胞壁合成 |
糖肽类抗生素Glycopeptides | 抑制细菌细胞壁合成 |
脂肽类抗生素Lipopeptides | 改变细菌细胞膜通透性 |
多黏菌素类抗生素Polymyxins | 改变细菌细胞膜通透性 |
氨基糖苷类抗生素Aminoglycosides | 抑制细菌蛋白质合成(作用30S 核糖体亚基) |
四环素类抗生素Tetracyclines | 抑制细菌蛋白质合成(作用30S 核糖体亚基) |
氯霉素类抗生素Chloramphenicol | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
林可酰胺类抗生素Lincosamides | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
大环内酯类抗生素Macrolides | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
恶唑烷酮类抗生素Oxazolidinones | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
链阳菌素类抗生素Streptogramins | 抑制细菌蛋白质合成(作用50S 核糖体亚基) |
喹诺酮类抗生素Quinolones | 抑制细菌核酸合成 |
磺胺类抗生素Sulfonamides | 抑制细菌代谢途径 |
甲氧苄啶Trimethoprim | 抑制细菌代谢途径 |
抗生素 Antibiotics | 渗透障碍 Uptake limitation | 靶位点改变 Target modification | 药物失活 Drug inactivation | 主动外排 Active drug efflux |
---|---|---|---|---|
β-内酰胺类抗生素β-Lactams | 孔蛋白减少或改变,细胞壁缺失 | PBPs改变 | β-内酰胺酶产生 | RND |
糖肽类抗生素Glycopeptides | 细胞壁增厚,细胞壁外层缺失 | 肽聚糖交联减少 | ||
氨基糖苷类抗生素Aminoglycosides | 细胞壁极性改变 | 核糖体突变、甲基化 | 氨基糖苷修饰酶,乙酰化、磷酰化和腺苷酰作用 | RND |
四环素类抗生素Tetracyclines | 孔蛋白减少 | 核糖体保护作用 | 抗生素修饰和氧化作用 | RND MFS |
氯霉素类抗生素Chloramphenicol | 核糖体甲基化 | 乙酰化作用 | RND MFS | |
林可酰胺类抗生素Lincosamides | 核糖体甲基化 | 核苷酸转移酶产生 | RND ABC | |
大环内酯类抗生素Macrolides | 核糖体突变、甲基化 | 糖苷酶、酯酶、磷酸化酶产生 | RND MFS ABC | |
恶唑烷酮类抗生素Oxazolidinones | 核糖体甲基化 | 乙酰基转移酶、水解酶、磷酸转移酶、核苷酸转移酶产生 | RND | |
喹诺酮类抗生素Quinolones | DNA促旋酶修饰,拓扑异构酶Ⅳ结构改变 | 乙酰化作用,磷酸转移酶产生 | MFS MATE | |
磺胺类抗生素Sulfonamides | DHPS亲和降低 | SadA和SadC产生 | RND | |
甲氧苄啶Trimethoprim | DHPS亲和降低 | RND | ||
多黏菌素类抗生素Polymyxins | 荚膜多糖增加 | 脂质A修饰改造 | 降解酶产生 | SMR |
表2 细菌耐药的类型和机制
Table 2 Types and mechanisms of antimicrobial resistance
抗生素 Antibiotics | 渗透障碍 Uptake limitation | 靶位点改变 Target modification | 药物失活 Drug inactivation | 主动外排 Active drug efflux |
---|---|---|---|---|
β-内酰胺类抗生素β-Lactams | 孔蛋白减少或改变,细胞壁缺失 | PBPs改变 | β-内酰胺酶产生 | RND |
糖肽类抗生素Glycopeptides | 细胞壁增厚,细胞壁外层缺失 | 肽聚糖交联减少 | ||
氨基糖苷类抗生素Aminoglycosides | 细胞壁极性改变 | 核糖体突变、甲基化 | 氨基糖苷修饰酶,乙酰化、磷酰化和腺苷酰作用 | RND |
四环素类抗生素Tetracyclines | 孔蛋白减少 | 核糖体保护作用 | 抗生素修饰和氧化作用 | RND MFS |
氯霉素类抗生素Chloramphenicol | 核糖体甲基化 | 乙酰化作用 | RND MFS | |
林可酰胺类抗生素Lincosamides | 核糖体甲基化 | 核苷酸转移酶产生 | RND ABC | |
大环内酯类抗生素Macrolides | 核糖体突变、甲基化 | 糖苷酶、酯酶、磷酸化酶产生 | RND MFS ABC | |
恶唑烷酮类抗生素Oxazolidinones | 核糖体甲基化 | 乙酰基转移酶、水解酶、磷酸转移酶、核苷酸转移酶产生 | RND | |
喹诺酮类抗生素Quinolones | DNA促旋酶修饰,拓扑异构酶Ⅳ结构改变 | 乙酰化作用,磷酸转移酶产生 | MFS MATE | |
磺胺类抗生素Sulfonamides | DHPS亲和降低 | SadA和SadC产生 | RND | |
甲氧苄啶Trimethoprim | DHPS亲和降低 | RND | ||
多黏菌素类抗生素Polymyxins | 荚膜多糖增加 | 脂质A修饰改造 | 降解酶产生 | SMR |
Ambler分类法 Ambler classification | Bush分类法 Bush classification | 代表酶 Representative β-lactamases | 底物 Substrates | 酶活中心 Active site |
---|---|---|---|---|
A类 Class A | 2a | 葡萄球菌酶 | 青霉素类 | 丝氨酸 |
2b | TEM-1,TEM-2,SHV-1 | 青霉素类和窄谱头孢菌素类 | ||
2be | TEM-10,SHV-2,CTX-M,GES-1 | 广谱青霉素与头孢菌素类 | ||
2br | TEM-30,SHV-72 | 青霉素类 | ||
2c | PSE | 青霉素类、羧苄青霉素 | ||
2e | CepA | 广谱头孢菌素类 | ||
2f | KPC,SEM,NMC-A,GFS-2 | 青霉素类、头孢菌素类、碳青霉烯类 | ||
B类Class B | 金属离子 | |||
B1 | 3a | IMP-1,NDM-1,VIM-1 | 亚胺培南、青霉素类、头孢菌素类 | |
B2 | 3b | CphA,Sfh-1 | 碳青霉烯类 | |
B3 | 3a | L1 | 头孢菌素类、碳青霉烯类 | |
3c | FEZ-1 | 头孢菌素类、碳青霉烯类 | ||
C类Class C | 1 | AmpC | 青霉素和头孢菌素类 | 丝氨酸 |
D类Class D | 2d | OXA-23,OXA-24,OXA-48 | 青霉素类和氯唑西林以及一些头孢菌素类和碳青霉烯类 | 丝氨酸 |
表3 主要β-内酰胺酶及分类
Ambler分类法 Ambler classification | Bush分类法 Bush classification | 代表酶 Representative β-lactamases | 底物 Substrates | 酶活中心 Active site |
---|---|---|---|---|
A类 Class A | 2a | 葡萄球菌酶 | 青霉素类 | 丝氨酸 |
2b | TEM-1,TEM-2,SHV-1 | 青霉素类和窄谱头孢菌素类 | ||
2be | TEM-10,SHV-2,CTX-M,GES-1 | 广谱青霉素与头孢菌素类 | ||
2br | TEM-30,SHV-72 | 青霉素类 | ||
2c | PSE | 青霉素类、羧苄青霉素 | ||
2e | CepA | 广谱头孢菌素类 | ||
2f | KPC,SEM,NMC-A,GFS-2 | 青霉素类、头孢菌素类、碳青霉烯类 | ||
B类Class B | 金属离子 | |||
B1 | 3a | IMP-1,NDM-1,VIM-1 | 亚胺培南、青霉素类、头孢菌素类 | |
B2 | 3b | CphA,Sfh-1 | 碳青霉烯类 | |
B3 | 3a | L1 | 头孢菌素类、碳青霉烯类 | |
3c | FEZ-1 | 头孢菌素类、碳青霉烯类 | ||
C类Class C | 1 | AmpC | 青霉素和头孢菌素类 | 丝氨酸 |
D类Class D | 2d | OXA-23,OXA-24,OXA-48 | 青霉素类和氯唑西林以及一些头孢菌素类和碳青霉烯类 | 丝氨酸 |
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