Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis Pub Date : 2025-01-01 DOI:10.1016/j.tube.2024.102592

Jiuyu Liu , Gregory A. Phelps , Christine M. Dunn , Patricia A. Murphy , Laura A. Wilt , Victoria Loudon , Robin B. Lee , Dinesh Fernando , Lei Yang , Kristina N. Tran , Brennen T. Troyer , Andres Obregon-Henao , Richard E. Lee

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引用次数: 0

Abstract

Tetracycline analogs from the minocycline family have recently shown promise for the treatment of non-tuberculous mycobacterial infections. However, current tetracycline and minocycline therapeutics can be limited by tolerability, stability, or inactivation by TetX. In this study, a series of novel 9-heteroaryl substituted minocycline analogs were designed and synthesized, which resulted in analogs with good in vitro activity against Mycobacterium tuberculosis and Mycobacterium abscessus, stability in water for more than 7 days, avoidance of TetX inactivation in M. abscessus, and a lack of cytotoxicity in HepG2 mammalian cells. In vivo efficacy was confirmed for the tetracycline analogs in an acute model of GM-CSF KO mice infected with M. abscessus, displaying superior efficacy to standard-of-care antibiotic clarithromycin. Molecular modeling and potentiation assays demonstrate avoidance of MabTetX, and the structure-activity relationships of the series are discussed herein for M. tuberculosis and M. abscessus.

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开发四环素类似物，提高水稳定性治疗分枝杆菌感染。

来自二甲胺四环素家族的四环素类似物最近显示出治疗非结核分枝杆菌感染的希望。然而，目前的四环素和二甲胺四环素治疗可能受到耐受性、稳定性或TetX失活的限制。本研究设计并合成了一系列新型的9-杂芳基取代米诺环素类似物，这些类似物对结核分枝杆菌和脓肿分枝杆菌具有良好的体外活性，在水中的稳定性超过7天，避免了脓肿分枝杆菌中TetX的失活，并且对HepG2哺乳动物细胞没有细胞毒性。四环素类似物在GM-CSF感染脓疱杆菌的KO小鼠急性模型中证实了体内疗效，显示出优于标准护理抗生素克拉霉素的疗效。分子模拟和增强实验表明，MabTetX对结核分枝杆菌和脓肿分枝杆菌没有作用，本文讨论了该系列的结构-活性关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tuberculosis 医学-呼吸系统

CiteScore

4.60

自引率

3.10%

发文量

审稿时长

49 days

期刊介绍： Tuberculosis is a speciality journal focusing on basic experimental research on tuberculosis, notably on bacteriological, immunological and pathogenesis aspects of the disease. The journal publishes original research and reviews on the host response and immunology of tuberculosis and the molecular biology, genetics and physiology of the organism, however discourages submissions with a meta-analytical focus (for example, articles based on searches of published articles in public electronic databases, especially where there is lack of evidence of the personal involvement of authors in the generation of such material). We do not publish Clinical Case-Studies. Areas on which submissions are welcomed include: -Clinical TrialsDiagnostics- Antimicrobial resistance- Immunology- Leprosy- Microbiology, including microbial physiology- Molecular epidemiology- Non-tuberculous Mycobacteria- Pathogenesis- Pathology- Vaccine development. This Journal does not accept case-reports. The resurgence of interest in tuberculosis has accelerated the pace of relevant research and Tuberculosis has grown with it, as the only journal dedicated to experimental biomedical research in tuberculosis.