Gentamicin

Gentamicin is an aminoglycoside bactericidal antibiotic that is effective against Gram-negative bacterial infections. Gentamicin binds to the 30S subunit of the bacterial ribosome to inhibit protein synthesis.

Exposure to 100 uM gentamicin exhibited a muscimol EC50 of 80 6nM (n=10). The EC50 value obtained in the absence of gentamicin was 124 11nM (n=10). The 35% increase in potency suggests network sensitization to muscimol in the presence of gentamicin. Action potential (AP) waveform analyses of neurons exposed to gentamicin demonstrated a concentration-dependent decrease in AP amplitudes (extracellular recordings), possibly reflecting gentamicin effects on voltage-gated ion channels^[3].When design, synthesis characterization and evaluation of a fluorescent conjugate of the aminoglycoside antibiotic gentamicin, Related gentamicin conjugates studied quench in live kindney cells, and have been largely restricted to use in fixed (delipidated) cells^[5]. Gentamicin increases mitochondria-specific oxidative stress and rapidly destroys CORE, leading to marked mitochondrial fragmentation and ER-mitochondrial dissociation, which leads to poor UPR activation and proteotoxic cell death^[1].Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm.CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria^[4]. Strong PKB/Akt activation was observed in the organ of Corti following exposure to 50μM gentamicin for 6 h. In addition, PKC activation by 12-O-tetradecanoylphorbol-13-acetate protected outer hair cells from gentamicin induced cell death^[6].

In Pigmented guinea pigs, Gentamicin was detected in every cochlear cell type, but with spatiotemporal variability. One day after application, an intense staining reaction was found in all cell types except the spiral ganglion cells and the stria vascularis. Six days later, gentamicin staining intensities were additionally reduced in the nerve fibers and the spiral ligament^[2].In organ culture that metformin blocks the gentamicin-induced translocation of endonuclease G into the nucleus of outer hair cells and attenuates hair cell loss. In vivo, gentamicin treatment with 80, 100, or 130mg/kg body weight for 14 days induced significant threshold shifts^[7].

References:
[1]: Igwebuike C, Yaglom J, et,al. Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity. Cell Death Dis. 2020 Apr 3;11(4):217. doi: 10.1038/s41419-020-2382-7. PMID: 32245975; PMCID: PMC7125232.
[2]: Heinrich UR, Schmidtmann I, et,al. Cell-specific accumulation patterns of gentamicin in the guinea pig cochlea. Hear Res. 2015 Aug;326:40-8. doi: 10.1016/j.heares.2015.03.010. Epub 2015 Apr 13. PMID: 25882166.
[3]: Hamilton KS, Gopal KV, et,al. Pharmacological response sensitization in nerve cell networks exposed to the antibiotic gentamicin. Eur J Pharmacol. 2017 Jan 5;794:92-99. doi: 10.1016/j.ejphar.2016.11.017. Epub 2016 Nov 15. PMID: 27864104.
[4]: Gomarasca M, F C Martins T, et,al.Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens. Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02545-16. doi: 10.1128/AAC.02545-16. PMID: 28096156; PMCID: PMC5365713.
[5]: Escobedo JO, Chu YH, et,al. Live cell imaging of a fluorescent gentamicin conjugate. Nat Prod Commun. 2012 Mar;7(3):317-20. PMID: 22545403; PMCID: PMC3376166.
[6]: Chung WH, Pak K, et,al. A PI3K pathway mediates hair cell survival and opposes gentamicin toxicity in neonatal rat organ of Corti. J Assoc Res Otolaryngol. 2006 Dec;7(4):373-82. doi: 10.1007/s10162-006-0050-y. Epub 2006 Oct 20. PMID: 17053865; PMCID: PMC2504631.
[7]: Oishi N, Kendall A, et,al. Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett. 2014 Nov 7;583:65-9. doi: 10.1016/j.neulet.2014.09.028. Epub 2014 Sep 18. PMID: 25240593; PMCID: PMC4253637.

庆大霉素是一种氨基糖苷类杀菌抗生素，可有效对抗革兰氏阴性细菌感染。庆大霉素与细菌核糖体30S亚基结合，抑制蛋白质合成。

暴露于 100 uM 庆大霉素后，蝇蕈醇 EC50 为 80 6nM (n=10)。在庆大霉素不存在下获得的 EC50 值为 124 11nM (n=10)。效力增加 35% 表明在庆大霉素存在下网络对蝇蕈醇敏感。暴露于庆大霉素的神经元的动作电位 (AP) 波形分析表明 AP 振幅（细胞外记录）呈浓度依赖性降低，可能反映了庆大霉素对电压门控离子通道的影响^[3]。在设计时，氨基糖苷类抗生素庆大霉素的荧光偶联物的合成表征和评估，相关庆大霉素偶联物在活肾细胞中进行了淬灭研究，并且在很大程度上仅限于在固定（脱脂）细胞中使用^[5]。庆大霉素增加线粒体特异性氧化应激并迅速破坏 CORE，导致显着的线粒体断裂和 ER-线粒体解离，从而导致 UPR 激活不良和蛋白毒性细胞死亡^[1]。细胞穿透肽 (CPP) ) 介导生物活性分子内化到细胞质中。CPPs 与庆大霉素共价偶联，CPP-庆大霉素偶联物用于靶向感染细胞以杀死多种细胞内革兰氏阴性致病菌^[4]。在暴露于 50μM 庆大霉素 6 小时后，在 Corti 器官中观察到强烈的 PKB/Akt 激活。此外，12-O-tetradecanoylphorbol-13-acetate 激活 PKC 可保护外毛细胞免受庆大霉素诱导的细胞死亡^[6]。

在有色豚鼠中，庆大霉素在每种耳蜗细胞类型中均被检测到，但具有时空变异性。应用一天后，在除螺旋神经节细胞和血管纹外的所有细胞类型中都发现了强烈的染色反应。六天后，庆大霉素染色强度在神经纤维和螺旋韧带^[2]中进一步降低。在器官培养中，二甲双胍阻断庆大霉素诱导的核酸内切酶 G 易位到外毛细胞核中并减轻毛细胞损失。在体内，庆大霉素以 80、100 或 130mg/kg 体重处理 14 天可引起显着的阈值变化^[7]。