Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland.
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden.
EBioMedicine. 2021 Nov;73:103652. doi: 10.1016/j.ebiom.2021.103652. Epub 2021 Nov 2.
The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP).
A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP.
EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin.
This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API.
A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
处于临床阶段的候选药物 EBL-1003（阿普拉霉素）代表了一类用于治疗耐药感染的新型氨基糖苷类抗生素。它对耐药分离株具有最佳的覆盖范围，并且在肺部感染模型中具有初步的疗效。然而，尚未提供其在其他疾病适应证中的效用的临床前证据。在这里，我们研究了 EBL-1003 在治疗复杂尿路感染和急性肾盂肾炎（cUTI/AP）中的治疗潜力。
我们使用数据库挖掘、抗菌药物敏感性测试、时间杀伤实验以及四种鼠类感染模型，对 EBL-1003 对革兰氏阴性尿路病原体的微生物覆盖范围和疗效进行了全面评估。我们研究了 EBL-1003 在大鼠中的药代动力学和肾毒性，以评估 EBL-1003 在治疗 cUTI/AP 中的治疗窗口。
EBL-1003 对包括氨基糖苷类耐药临床分离株在内的多种细菌尿路病原体具有广谱活性和快速的多对数 CFU 减少。阿普拉霉素分子中的胺基碱性表明，与庆大霉素或阿米卡星相比，在尿液 pH 值下正电荷增加更高，从而导致持续的药物摄取和杀菌活性，因此在鼠类感染模型中具有强大的疗效。成年大鼠的肾药代动力学、毒性生物标志物和肾脏组织病理学均表明，EBL-1003 的肾毒性明显低于庆大霉素。
这项研究为 EBL-1003 在 cUTI/AP 中的疗效提供了临床前概念验证。与庆大霉素相比，EBL-1003 的疗效相似但肾毒性较低，这可能转化为治疗 cUTI/AP 时更高的安全性和更宽的治疗窗口。
可以在致谢部分找到为本研究做出贡献的所有资助机构的完整列表。
