Dinos George P
Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece.
Br J Pharmacol. 2017 Sep;174(18):2967-2983. doi: 10.1111/bph.13936. Epub 2017 Aug 10.
Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.
大环内酯类药物是一大类蛋白质合成抑制剂，因其在人类医学中的适用性而具有重大临床意义。大环内酯类由不同环大小的大环内酯组成，其上连接有一个或多个脱氧糖或氨基糖残基。大环内酯类通过与细菌50S核糖体亚基结合并干扰蛋白质合成来发挥抗生素作用。大环内酯类对细菌核糖体的高亲和力，以及几乎所有细菌物种核糖体的高度保守结构，与其广谱活性相一致。自1950年发现第一代大环内酯类药物红霉素以来，已合成了许多衍生物，产生了生物利用度更高、酸稳定性更好且药代动力学得到改善的化合物。这些努力催生了第二代大环内酯类药物，包括阿奇霉素和克拉霉素等知名成员。随后，为应对日益增加的抗生素耐药性，开发了第三代大环内酯类药物，其对许多大环内酯耐药菌株具有更好的活性。然而，这些改进伴随着严重的副作用，令人失望，导致许多研究人员停止对大环内酯类衍生物的研究，认为这一过程已走到尽头。相比之下，最近发表的一项突破为合成和发现多种不同的大环内酯类抗生素引入了一个新的化学平台。这种化学合成革命，再加上副作用（即“泰利霉素效应”）的减少，引发了大环内酯类药物的复兴，增加了对抗严重人类传染病的新型安全治疗药物的希望。
