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Abstract：
Mycobacterium tuberculosis (Mtb) as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug resistance. The loss of antibiotic efficacy has raised interest in the identification of host-directed therapeutics (HDT) to develop novel treatment strategies for mycobacterial infections. In this study, we identified amiodarone as a potential HDT candidate that inhibited both intracellular Mtb and Mycobacterium avium in primary human macrophages without directly impairing bacterial growth, thereby confirming that amiodarone acts in a host-mediated manner. Moreover, amiodarone induced the formation of (auto)phagosomes and enhanced autophagic targeting of mycobacteria in macrophages. The induction of autophagy by amiodarone is likely due to enhanced transcriptional regulation, as the nuclear intensity of the transcription factor EB, the master regulator of autophagy and lysosomal biogenesis, was strongly increased. Furthermore, blocking lysosomal degradation with bafilomycin impaired the host-beneficial effect of amiodarone. Finally, amiodarone induced autophagy and reduced bacterial burden in a zebrafish embryo model of tuberculosis, thereby confirming the HDT activity of amiodarone in vivo. In conclusion, we have identified amiodarone as an autophagy-inducing antimycobacterial HDT that improves host control of mycobacterial infections.
OBJECTIVE: Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of Mtb and Mycobacterium avium in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an in vivo tuberculosis model based on Mycobacterium marinum infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
OBJECTIVE: Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of Mtb and Mycobacterium avium in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an in vivo tuberculosis model based on Mycobacterium marinum infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
摘要：
结核分枝杆菌（Mtb）和非结核分枝杆菌是细胞内病原体，由于分枝杆菌耐药性的上升，其治疗广泛且日益受到损害。抗生素功效的丧失引起了人们对鉴定宿主定向疗法（HDT）以开发分枝杆菌感染的新型治疗策略的兴趣。在这项研究中,我们确定胺碘酮是一种潜在的HDT候选物，可以抑制原代人巨噬细胞中的细胞内Mtb和分枝杆菌，而不会直接损害细菌生长，从而证实胺碘酮以宿主介导的方式起作用。此外，胺碘酮诱导（自）吞噬体的形成并增强巨噬细胞中分枝杆菌的自噬靶向。胺碘酮诱导自噬可能是由于增强的转录调节，作为转录因子EB的核强度，自噬和溶酶体生物发生的主要调节因子，强烈增加。此外，用bafilomycin阻断溶酶体降解损害了胺碘酮对宿主的有益作用。最后,胺碘酮在斑马鱼结核病胚胎模型中诱导自噬并减少细菌负担，从而证实胺碘酮在体内的HDT活性。总之,我们发现胺碘酮是一种诱导自噬的抗分枝杆菌HDT,可改善宿主对分枝杆菌感染的控制.
目的：由于全球抗生素耐药性上升，非常需要针对细胞内细菌感染的替代治疗策略，包括结核分枝杆菌(Mtb)和非结核分枝杆菌。通过宿主导向疗法（HDT）刺激宿主防御机制是治疗分枝杆菌感染的有希望的方法。这项研究确定了胺碘酮，抗心律失常药,作为抑制Mtb和鸟分枝杆菌在原代人巨噬细胞中存活的潜在HDT候选物。在基于斑马鱼胚胎的marinum分枝杆菌感染的体内结核病模型中证实了胺碘酮的抗分枝杆菌作用。此外，胺碘酮诱导的自噬和自噬通量的抑制有效地削弱了胺碘酮的宿主保护作用，支持宿主（自）吞噬溶酶体途径的激活对于胺碘酮的作用机制至关重要。总之,我们已经确定胺碘酮是一种诱导自噬的HDT,可改善宿主对多种分枝杆菌的控制.
目的：由于全球抗生素耐药性上升，非常需要针对细胞内细菌感染的替代治疗策略，包括结核分枝杆菌(Mtb)和非结核分枝杆菌。通过宿主导向疗法（HDT）刺激宿主防御机制是治疗分枝杆菌感染的有希望的方法。这项研究确定了胺碘酮，抗心律失常药,作为抑制Mtb和鸟分枝杆菌在原代人巨噬细胞中存活的潜在HDT候选物。在基于斑马鱼胚胎的marinum分枝杆菌感染的体内结核病模型中证实了胺碘酮的抗分枝杆菌作用。此外，胺碘酮诱导的自噬和自噬通量的抑制有效地削弱了胺碘酮的宿主保护作用，支持宿主（自）吞噬溶酶体途径的激活对于胺碘酮的作用机制至关重要。总之,我们已经确定胺碘酮是一种诱导自噬的HDT,可改善宿主对多种分枝杆菌的控制.
