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.

抗菌素耐药性的蔓延和新型抗生素的短缺导致迫切需要新的抗菌剂。尽管氨基糖苷类抗生素 (AGs) 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。我们评估了从更大的一组 AG 中选择的各种 AG 的耳毒性，这些 AG 对 ESKAPE 小组的多药耐药临床分离株具有强大的抗菌活性：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，AGs 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 C1a 和安普霉素毒性最小。引人注目的是，尽管在用低浓度的新霉素、庆大霉素和巴龙霉素处理后，复合动作电位阈值和外毛细胞存活率没有变化，但内毛细胞突触带的数量和复合动作电位幅度降低了。这种浓度的庆大霉素 C1a 或安普霉素没有观察到这种隐性听力损失的迹象。这些发现确定内毛细胞是 AG 治疗最脆弱的元素，表明庆大霉素 C1a 和安普霉素是开发临床有用抗生素的有希望的基础。这种浓度的庆大霉素 C1a 或安普霉素没有观察到这种隐性听力损失的迹象。这些发现确定内毛细胞是 AG 治疗最脆弱的元素，表明庆大霉素 C1a 和安普霉素是开发临床有用抗生素的有希望的基础。这种浓度的庆大霉素 C1a 或安普霉素没有观察到这种隐性听力损失的迹象。这些发现确定内毛细胞是 AG 治疗最脆弱的元素，表明庆大霉素 C1a 和安普霉素是开发临床有用抗生素的有希望的基础。