In vivo screening for toxicity-modulating drug interactions identifies antagonism that protects against ototoxicity in zebrafish.
In vivo screening for toxicity-modulating drug interactions identifies antagonism that protects against ototoxicity in zebrafish.
复制标题
毒性调节药物相互作用的体内筛选确定了防止斑马鱼耳毒性的拮抗作用。
DOI：
10.1101/2023.11.08.566159
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ma,Shuyi
中科院分区：
文献类型：
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作者：
Bustad,Ethan;Mudrock,Emma;Nilles,ElizabethM;McQuate,Andrea;Bergado,Monica;Gu,Alden;Galitan,Louie;Gleason,Natalie;Ou,HenryC;Raible,DavidW;Hernandez,RafaelE;Ma,Shuyi
前言：耳毒性是150多种具有不同作用机制的药物的减弱性副作用，其中许多药物可以同时用于治疗多种疾病。临床前评估可能影响耳毒性的药物-药物相互作用的方法将有助于设计更安全的多药方案，并通过标记可能导致不良相互作用的组合来减少不安全的多药联用，以便进行监测。方法：为了满足这一需求，我们开发了一种新的工作流程，称为用于毒性评估的保护和损伤并行评估(PEITA)，它使得通过显微镜高通量、半自动地定量斑马鱼幼体的耳毒性和耳保护成为可能。我们利用Pepita和共聚焦显微镜在体内研究了药物相互作用对斑马鱼侧线毛细胞的耳毒性药物摄取和细胞损伤的影响。结果与讨论：通过应用Pepita来衡量耳毒性药物相互作用的结果，我们发现了大环内酯类和氨基糖苷类抗生素之间的拮抗作用，对氨基糖苷类药物引起的斑马鱼侧线毛细胞损伤具有保护作用。在斑马鱼体内联合应用阿奇霉素或红霉素可保护其免受广泛氨基糖苷类药物的损害，至少部分是通过独立于毛细胞机械转导的机制抑制药物进入毛细胞。相反，在细菌抑制试验中，大环内酯类化合物与氨基糖苷类化合物联合使用并不显示出抗菌效果的拮抗作用。概念验证的耳保护性拮抗表明，可以潜在地开发组合干预措施，以防止其他形式的毒性，而不会阻碍靶向药物的疗效。
Introduction:Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury.Methods:To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells.Results and discussion:By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycoside-induced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy.