Isoniazid and nicotinic hydrazide hybrids mitigate trehalose-6,6'-dimycolate-induced inflammatory responses and pulmonary granulomas via Syk/PI3K pathways: A promising host-directed therapy for tuberculosis

Ha-Yeon Song; Bo-Gyeong Yoo; Yuna Lee; Jae Yoon Lim; Eun Ji Gu; Jongho Jeon; Eui-Baek Byun

doi:10.1016/j.biopha.2024.117798

Isoniazid and nicotinic hydrazide hybrids mitigate trehalose-6,6'-dimycolate-induced inflammatory responses and pulmonary granulomas via Syk/PI3K pathways: A promising host-directed therapy for tuberculosis

Biomed Pharmacother. 2025 Jan 6:183:117798. doi: 10.1016/j.biopha.2024.117798. Online ahead of print.

Authors

Ha-Yeon Song¹, Bo-Gyeong Yoo², Yuna Lee¹, Jae Yoon Lim³, Eun Ji Gu⁴, Jongho Jeon⁴, Eui-Baek Byun⁵

Affiliations

¹ Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea.
² 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.
³ Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea; Department of Food and Nutrition, Chungnam National University, Daejeon 34134, Republic of Korea.
⁴ Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 41566, Republic of Korea.
⁵ Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Republic of Korea. Electronic address: ebbyun80@kaeri.re.kr.

PMID: 39764922
DOI: 10.1016/j.biopha.2024.117798

Abstract

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.

Keywords: Anti-inflammation; Host-directed therapy; Isoniazid hybrids; Pulmonary granuloma; Trehalose-6,6’-dimycolate; Tuberculosis.