Hainrichson Mariana, Nudelman Igor, Baasov Timor
The Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Org Biomol Chem. 2008 Jan 21;6(2):227-39. doi: 10.1039/b712690p. Epub 2007 Oct 9.
Aminoglycosides are highly potent, broad-spectrum antibiotics that exert their bactericidal therapeutic effect by selectively binding to the decoding aminoacyl site (A-site) of the bacterial 16 S rRNA, thereby interfering with translational fidelity during protein synthesis. The appearance of bacterial strains resistant to these drugs, as well as their relative toxicity, have inspired extensive searches towards the goal of obtaining novel molecular designs with improved antibacterial activity and reduced toxicity. In the last few years, a new, aminoglycoside dependent therapeutic approach for the treatment of certain human genetic diseases has been identified. These treatments rely on the ability of certain aminoglycosides to induce mammalian ribosomes to readthrough premature stop codon mutations. This new and challenging task has introduced fresh research avenues in the field of aminoglycoside research. Recent observations and current challenges in the design of aminoglycosides with improved antibacterial activity and the treatment of human genetic diseases are discussed.
氨基糖苷类是高效、广谱抗生素，通过选择性结合细菌16S rRNA的解码氨酰位点（A位点）发挥杀菌治疗作用，从而干扰蛋白质合成过程中的翻译保真度。对这些药物产生耐药性的细菌菌株的出现以及它们相对的毒性，激发了人们为获得具有改善抗菌活性和降低毒性的新型分子设计而进行的广泛探索。在过去几年中，已确定了一种用于治疗某些人类遗传疾病的新的氨基糖苷类依赖治疗方法。这些治疗依赖于某些氨基糖苷类诱导哺乳动物核糖体通读过早终止密码子突变的能力。这项新的具有挑战性的任务为氨基糖苷类研究领域引入了新的研究途径。本文讨论了在设计具有改善抗菌活性的氨基糖苷类以及治疗人类遗传疾病方面的最新观察结果和当前挑战。
