Antimicrobial resistance in tuberculosis (TB) is a public health threat of global dimension, worsened by increasing drug resistance. Host-directed therapy (HDT) is an emerging concept currently explored as an adjunct therapeutic strategy for TB. One potential host target is the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which binds TB virulence factors and controls antibacterial responses. Here, we demonstrate that in the context of therapy, the AhR binds several TB drugs, including front line drugs rifampicin (RIF) and rifabutin (RFB), resulting in altered host defense and drug metabolism. AhR sensing of TB drugs modulates host defense mechanisms, notably impairs phagocytosis, and increases TB drug metabolism. Targeting AhR in vivo with a small-molecule inhibitor increases RFB-treatment efficacy. Thus, the AhR markedly impacts TB outcome by affecting both host defense and drug metabolism. As a corollary, we propose the AhR as a potential target for HDT in TB in adjunct to canonical chemotherapy.

中文翻译：

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结核药物对芳烃受体的调节会损害宿主的防御和治疗效果。

结核病（TB）的抗菌素耐药性是全球性的公共卫生威胁，由于耐药性的增加而恶化。宿主定向治疗（HDT）是一种新兴的概念，目前正在作为结核病的辅助治疗策略进行探索。一种潜在的宿主靶标是配体激活的转录因子芳烃受体（AhR），该受体与TB致病因子结合并控制抗菌反应。在这里，我们证明了在治疗的背景下，AhR结合了几种结核病药物，包括一线药物利福平（RIF）和利福布汀（RFB），导致宿主防御和药物代谢发生改变。AhR感测结核病药物可调节宿主防御机制，特别是损害吞噬作用，并增加结核病药物的代谢。用小分子抑制剂体内靶向AhR可提高RFB治疗的功效。因此，AhR通过影响宿主防御和药物代谢显着影响结核病预后。作为推论，我们建议在常规化学疗法的辅助下，将AhR作为TB HDT的潜在靶标。