PUBLICATION

Host-directed therapy with amiodarone in preclinical models restricts mycobacterial infection and enhances autophagy

Authors
Kilinç, G., Boland, R., Heemskerk, M.T., Spaink, H.P., Haks, M.C., van der Vaart, M., Ottenhoff, T.H.M., Meijer, A.H., Saris, A.
ID
ZDB-PUB-240626-2
Date
2024
Source
Microbiology spectrum   12(8): e0016724 (Journal)
Registered Authors
Boland, Ralf, Meijer, Annemarie H., Spaink, Herman P., van der Vaart, Michiel
Keywords
Mycobacterium avium, Mycobacterium marinum, Mycobacterium tuberculosis, amiodarone, host-directed therapy, human macrophages, zebrafish
MeSH Terms
  • Zebrafish*/microbiology
  • Animals
  • Mycobacterium tuberculosis*/drug effects
  • Mycobacterium tuberculosis*/growth & development
  • Amiodarone*/pharmacology
  • Lysosomes/drug effects
  • Lysosomes/metabolism
  • Lysosomes/microbiology
  • Disease Models, Animal
  • Autophagy*/drug effects
  • Macrophages*/drug effects
  • Macrophages*/immunology
  • Macrophages*/microbiology
  • Humans
  • Tuberculosis*/drug therapy
  • Tuberculosis*/microbiology
  • Mycobacterium avium/drug effects
(all 17)
PubMed
38916320 Full text @ Microbiol Spectr
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.
Importance 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.
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Allele Construct Type Affected Genomic Region
gl22TgTransgenic Insertion
    i114TgTransgenic Insertion
      ump2TgTransgenic Insertion
        zf155TgTransgenic Insertion
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          Marker Marker Type Name
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          Citation
          Kilinç, G., Boland, R., Heemskerk, M.T., Spaink, H.P., Haks, M.C., van der Vaart, M., Ottenhoff, T.H.M., Meijer, A.H., Saris, A. (2024) Host-directed therapy with amiodarone in preclinical models restricts mycobacterial infection and enhances autophagy. Microbiology spectrum. 12(8):e0016724.