Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
Infection. 2021 Feb;49(1):29-56. doi: 10.1007/s15010-020-01536-y. Epub 2020 Dec 23.
Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes.
This review summarizes data describing multiple modes of action of antibiotics in eukaryotes.
Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones.
The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
选择性毒性抗生素被认为是由于与细菌特有的靶点相互作用，或者由于原核和真核途径之间存在二分法，即药物与细菌靶点的亲和力高于真核靶点。然而，选择性毒性理论过于简化了抗生素在原核和真核生物中的复杂作用模式。
本综述总结了描述抗生素在真核生物中多种作用模式的资料。
氨基糖苷类、大环内酯类、恶唑烷酮类、氯霉素、克林霉素、四环素类、甘氨酰环素类、氟喹诺酮类、利福平、贝达喹啉、β-内酰胺类通过与线粒体结合、抑制线粒体 RNA 聚合酶、拓扑异构酶 2β、ATP 合成、转运体活性，抑制线粒体翻译。恶唑烷酮类、四环素类、万古霉素、β-内酰胺类、杆菌肽、异烟肼、硝呋太尔抑制基质金属蛋白酶（MMP）是因为与锌和钙螯合，而氟喹诺酮类和氯霉素也与这些阳离子螯合，但增加了 MMP 活性。MMP 抑制支持了β-内酰胺类和达托霉素在皮肤感染中的临床疗效，以及大环内酯类、四环素类在呼吸道疾病中的临床疗效。螯合作用可能有助于β-内酰胺类和氟喹诺酮类的神经保护作用。氨基糖苷类、大环内酯类、氯霉素、恶唑烷酮类、四环素类导致过早终止密码子通读。已经在人类细胞中鉴定出抗生素的其他一些靶点，如氟喹诺酮类与真核生物的 DNA 损伤修复相互作用，或恶唑烷酮类抑制粘蛋白过度产生。
抗生素对真核生物的作用是由于原核和真核靶点的结构和功能同源性，导致其抗菌活性的相同机制，因此抗生素对哺乳动物的作用是其整体作用机制的组成部分。
