Song Ha-Yeon, Yoo Bo-Gyeong, Lee Yuna, Lim Jae Yoon, Gu Eun Ji, Jeon Jongho, Byun Eui-Baek
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea.
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; Department of Food Science and Technology, Kongju National University, Yesan 32439, Republic of Korea.
Biomed Pharmacother. 2025 Feb;183:117798. doi: 10.1016/j.biopha.2024.117798. Epub 2025 Jan 6.
Granulomas, dense clusters of immune cells and bacteria, are critical barriers in tuberculosis (TB) treatment. Recent advancements in TB management have highlighted granuloma control as a potential host-directed therapy (HDT) strategy. Although isoniazid (INH) is the first-line drug for TB therapy, its efficacy is limited to non-replicating Mycobacterium tuberculosis (Mtb) under granulomatous conditions, necessitating the development of more effective derivatives. In this study, hybrid compounds of isoniazid, designated as INH-D1 and INH-D2, were synthesized and evaluated for their effects on controlling inflammatory responses and pulmonary granuloma lesions induced by trehalose-6,6'-dimycolate (TDM), a glycolipid of Mtb. Both INH-D1 and INH-D2 demonstrated stronger inhibitory effects on inflammatory mediators (TNF-α, interleukin-6, co-stimulatory molecules, and MHC class I) in TDM-stimulated macrophages compared to original INH. These anti-inflammatory effects were mediated by the inhibition of Syk, p38, PI3K, and NF-κB transcription. INH-D1 and INH-D2 exhibited stronger binding energies to Syk and PI3Kα/β than INH, which are known as proximal kinases and key mediator in TDM-mediated inflammatory responses. Oral administration of INH-D2 successfully relieved TDM-induced pulmonary granuloma pathology by reducing innate immune cell infiltration, hypoxic conditions in the lungs, and systemic inflammation by decreasing serum cytokines and chemokines. In contrast, original INH and INH-D1 did not effectively alleviate pulmonary granuloma pathology. These findings demonstrate that the novel molecule INH-D2 is effective in treating pulmonary granulomas owing to its strong anti-inflammatory effects, highlighting it as a promising HDT candidate for the management of pulmonary tuberculosis, thereby providing a strategic alternative to standard anti-TB antibiotics.
肉芽肿是免疫细胞和细菌的密集簇，是结核病治疗中的关键屏障。结核病管理的最新进展突出了肉芽肿控制作为一种潜在的宿主导向疗法（HDT）策略。尽管异烟肼（INH）是结核病治疗的一线药物，但其疗效仅限于肉芽肿条件下非复制型结核分枝杆菌（Mtb），因此需要开发更有效的衍生物。在本研究中，合成了异烟肼的杂合化合物，命名为INH-D1和INH-D2，并评估了它们对由Mtb糖脂海藻糖-6,6'-二甲酯（TDM）诱导的炎症反应和肺肉芽肿病变的控制作用。与原始INH相比，INH-D1和INH-D2对TDM刺激的巨噬细胞中的炎症介质（TNF-α、白细胞介素-6、共刺激分子和MHC I类）均表现出更强的抑制作用。这些抗炎作用是通过抑制Syk、p38、PI3K和NF-κB转录介导的。INH-D1和INH-D2与Syk和PI3Kα/β的结合能比INH更强，而Syk和PI3Kα/β是TDM介导的炎症反应中的近端激酶和关键介质。口服INH-D2通过减少先天免疫细胞浸润、肺部缺氧状况以及通过降低血清细胞因子和趋化因子减轻全身炎症，成功缓解了TDM诱导的肺肉芽肿病理。相比之下，原始INH和INH-D1未能有效减轻肺肉芽肿病理。这些发现表明，新型分子INH-D2因其强大的抗炎作用在治疗肺肉芽肿方面有效，突出了它作为治疗肺结核的有前景的HDT候选药物，从而为标准抗结核抗生素提供了一种战略替代方案。
