Department of Biological Sciences and Institute of Life Sciences, Kangwon National University, Chuncheon, Republic of Korea.
College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.
PLoS One. 2019 Mar 13;14(3):e0199799. doi: 10.1371/journal.pone.0199799. eCollection 2019.
Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major health problem worldwide. Thus, identification of new and more effective drugs to treat emerging multidrug-resistant TB (MDR-TB) and to reduce the side effects of anti-TB drugs, such as liver toxicity and other detrimental changes, is urgently needed. In this study, to develop a novel candidate drug for effective TB treatment with few side effects in the host, we selected pasakbumin A isolated from Eurycoma longifolia (E. longifolia) Jack, which protected host cells against Mtb infection-induced death. Pasakbumin A significantly inhibited intracellular Mtb growth by inducing the autophagy via the ERK1/2-mediated signaling pathway in Mtb-infected macrophages. We further investigated whether pasakbumin A could be used as a potential adjuvant for TB treatment. Treatment with pasakbumin A and anti-TB drug rifampicin (RMP) potently suppressed intracellular Mtb killing by promoting autophagy as well as TNF-α production via the ERK1/2- and NF-κB-mediated signaling pathways in Mtb-infected cells. Our results suggest that pasakbumin A could be developed as a novel anti-TB drug or host-directed therapeutic (HDT) strategy to protect against host cell death and improve host defense mechanisms against Mtb infection in macrophages.
结核病（TB）是一种由结核分枝杆菌（Mtb）引起的慢性传染病，仍然是全球主要的健康问题。因此，迫切需要发现新的、更有效的药物来治疗新出现的耐多药结核病（MDR-TB），并减少抗结核药物的副作用，如肝毒性和其他有害变化。在这项研究中，为了开发一种新型候选药物，用于有效治疗结核病且宿主副作用少，我们选择了从长柄铁心木（E. longifolia）Jack 中分离得到的 pasakbumin A，它可以保护宿主细胞免受 Mtb 感染诱导的死亡。Pasakbumin A 通过 ERK1/2 介导的信号通路诱导自噬，显著抑制了 Mtb 感染的巨噬细胞内的 Mtb 生长。我们进一步研究了 pasakbumin A 是否可用于潜在的结核病治疗。在 Mtb 感染的细胞中，pasakbumin A 与抗结核药物利福平（RMP）联合治疗通过 ERK1/2 和 NF-κB 介导的信号通路促进自噬和 TNF-α 产生，从而强力抑制了细胞内 Mtb 的杀伤。我们的研究结果表明，pasakbumin A 可以开发为一种新型的抗结核药物或宿主定向治疗（HDT）策略，以防止宿主细胞死亡并增强巨噬细胞中针对 Mtb 感染的宿主防御机制。
