Tuberculosis (TB) is a global epidemic that kills over a million people every year, particularly in low-resource communities. Mycobacterium tuberculosis, the most common bacterium that causes TB, is difficult to treat, particularly in its latent phase, in part due to its ability to survive and replicate within the host macrophage. New therapeutic approaches resulting in better tolerated and shorter antibiotic courses that target intracellular bacteria are critical to effective treatment. The development of a novel, pH-responsive, mannosylated nanoparticle, covalently linked with isoniazid, a first-line TB antibiotic, is presented. This nanoparticle drug delivery agent has increased macrophage uptake and, upon exposure to the acidic phagolysosome, releases isoniazid through hydrolysis of a hydrazone bond, and disintegrates into a linear polymer. Full antibiotic activity is shown to be retained, with mannosylated isoniazid particles being the only treatment exhibiting complete bacterial eradication of intracellular bacteria, compared to an equivalent PEGylated system and free isoniazid. Such a system, able to effectively kill intracellular mycobacteria, holds promise for improved outcomes in TB infection.

中文翻译：

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用于细胞内结核病治疗的双 pH 响应性巨噬细胞靶向异烟肼糖颗粒

结核病 (TB) 是一种全球流行病，每年导致超过 100 万人死亡，尤其是在资源匮乏的社区。结核分枝杆菌TB 是最常见的导致 TB 的细菌，难以治疗，特别是在潜伏期，部分原因是它能够在宿主巨噬细胞内存活和复制。导致针对细胞内细菌的更好耐受性和更短抗生素疗程的新治疗方法对于有效治疗至关重要。介绍了一种新型、pH 响应性甘露糖化纳米颗粒的开发，该纳米颗粒与一线结核病抗生素异烟肼共价连接。这种纳米颗粒药物递送剂增加了巨噬细胞的摄取，并且在暴露于酸性吞噬溶酶体时，通过腙键的水解释放异烟肼，并分解成线性聚合物。显示保留了完整的抗生素活性，与等效的聚乙二醇化系统和游离异烟肼相比，甘露糖化异烟肼颗粒是唯一一种表现出细胞内细菌完全细菌根除的治疗方法。这种能够有效杀死细胞内分枝杆菌的系统有望改善结核病感染的结果。