Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use
Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use
复制标题
DOI：
10.1038/s41598-019-38634-3
复制
发表时间：
2019-02-20
影响因子：
4.6
通讯作者：
Beatriz Duran-Alonso, M.
中科院分区：
文献类型：
--
作者：
Ishikawa, Masaaki;Garcia-Mateo, Nadia;Beatriz Duran-Alonso, M.
抗生素耐药性的蔓延和新型抗生素的短缺导致了对新抗菌药物的迫切需求。虽然氨基糖苷类抗生素（AG）是非常有效的抗感染药物，但由于严重的副作用，主要是肾毒性和耳毒性，它们的使用在很大程度上受到限制。我们评价了从更大的AG组中选择的各种AG的耳毒性，这些AG基于其对ESKAPE面板的多药耐药临床分离株的强抗菌活性：庆大霉素、庆大霉素C1a、安普霉素、巴龙霉素和新霉素。局部圆窗应用后，AG对外毛细胞存活和复合动作电位的剂量依赖性影响显示庆大霉素C1 a和安普霉素的毒性最小。引人注目的是，虽然没有观察到变化的复合动作电位阈值和外毛细胞的存活率与低浓度的新霉素，庆大霉素和巴龙霉素治疗后，内毛细胞突触带的数量和复合动作电位振幅减少。在这样的浓度下，庆大霉素C1a或安普霉素未观察到这种隐性听力损失的迹象。这些发现确定内毛细胞作为AG治疗的最脆弱的元素，表明庆大霉素C1a和安普霉素是有前途的基础，为临床上有用的抗生素的发展。
Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.