@article{fdi:010073232,
  title = {{A}utophagic-related cell death of {T}rypanosoma brucei induced by bacteriocin {AS}-48},
  author = {{M}artinez-{G}arcia, {M}. and {B}art, {J}ean-{M}athieu and {C}ampos-{S}alinas, {J}. and {V}aldivia, {E}. and {M}artinez-{B}ueno, {M}. and {G}onzalez-{R}ey, {E}. and {N}avarro, {M}. and {M}aqueda, {M}. and {C}ebrian, {R}. and {P}erez-{V}ictoria, {J}. {M}.},
  editor = {},
  language = {{ENG}},
  abstract = {{T}he parasitic protozoan {T}rypanosoma brucei is the causative agent of human {A}frican trypanosomiasis (sleeping sickness) and nagana. {C}urrent drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. {A}ntimicrobial peptides have recently attracted attention as potential parasiticidal compounds. {H}ere, we explore circular bacteriocin {AS}-48's ability to kill clinically relevant bloodstream forms of {T}. brucei gambiense, {T}. brucei rhodesiense and {T}. brucei brucei. {AS}-48 exhibited excellent anti-trypanosomal activity in vitro ({EC}50 = 1-3 n{M}) against the three {T}. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. {I}n contrast to its antibacterial action, {AS}-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. {T}his was evidenced by the fact that vital dye internalization-prohibiting concentrations of {AS}-48 could kill the parasite at 37 degrees {C} but not at 4 degrees {C}. {F}urthermore, {AS}-48 interacted with the surface of the parasite, at least in part via {VSG}, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of {AS}-48. {T}he bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. {T}hese changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as {AS}-48 induced the production of {EGFP}-{ATG}8.2-labeled autophagosomes. {C}ollectively, these results indicate {AS}-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of {VSG}-bound {AS}-48 and the induction of autophagic-like cell death. {A}s {AS}-48 has greater in vitro activity than the drugs currently used to treat {T}. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana.},
  keywords = {{T}rypanosoma brucei ; {A}ntimicrobial peptides ; {AS}-48 ; {A}utophagy ; {S}leeping sickness ; {T}rypanocidal drugs},
  booktitle = {},
  journal = {{I}nternational {J}ournal for {P}arasitology - {D}rugs and {D}rug {R}esistance},
  volume = {8},
  numero = {2},
  pages = {203--212},
  ISSN = {2211-3207},
  year = {2018},
  DOI = {10.1016/j.ijpddr.2018.03.002},
  URL = {https://www.documentation.ird.fr/hor/fdi:010073232},
}