School of Chemistry, Raymond and Beverley Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Bioorg Med Chem Lett. 2020 Jul 1;30(13):127218. doi: 10.1016/j.bmcl.2020.127218. Epub 2020 Apr 25.
Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.
氨基糖苷类抗生素，用于治疗持续性革兰氏阴性感染、结核病以及新生儿和囊性纤维化患者的危及生命的感染，可推断出急性肾损伤和不可逆的听力损失。导致氨基糖苷类抗生素毒性的细胞靶标和过程的全部范围尚未完全解决，这使得设计合理的方法来避免其不良反应具有挑战性。因此，在合理解决氨基糖苷类诱导的毒性问题方面几乎没有做出任何努力。本文概述了报道的氨基糖苷类对内耳细胞和肾小管上皮细胞的影响。我们描述了通过评估天然和半合成氨基糖苷类抗生素建立的结构-毒性关系的选定示例。讨论了用于评估这些抗生素的各种测定法和模型以及开发更安全的氨基糖苷类抗生素的最新进展。
