@article{fdi:010069469,
  title = {{I}nsight into the mechanism of action of temporin-{SH}a, a new broad-spectrum antiparasitic and antibacterial agent},
  author = {{R}aja, {Z}. and {A}ndre, {S}. and {A}bbassi, {F}. and {H}umblot, {V}. and {L}equin, {O}. and {B}ouceba, {T}. and {C}orreia, {I}. and {C}asale, {S}. and {F}oulon, {T}. and {S}ereno, {D}enis and {O}ury, {B}runo and {L}adram, {A}.},
  editor = {},
  language = {{ENG}},
  abstract = {{A}ntimicrobial peptides ({AMP}s) are promising drugs to kill resistant pathogens. {I}n contrast to bacteria, protozoan parasites, such as {L}eishmania, were little studied. {T}herefore, the antiparasitic mechanism of {AMP}s is still unclear. {I}n this study, we sought to get further insight into this mechanism by focusing our attention on temporin-{SH}a ({SH}a), a small broad-spectrum {AMP} previously shown to be active against {L}eishmania infantum. {T}o improve activity, we designed analogs of {SH}a and compared the antibacterial and antiparasitic mechanisms. [{K}-3] {SH}a emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids ({L}eishmania and {T}rypanosoma), with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of {S}. aureus and antimony-resistant {L}. infantum. {M}ultipassage resistance selection demonstrated that temporins-{SH}, particularly [{K}-3] {SH}a, are not prone to induce resistance in {E}scherichia coli. {A}nalysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. {T}his was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy). {M}ultiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry) allowed us to detail peptide-membrane interactions. [{K}-3] {SH}a was shown to interact selectively with anionic model membranes with a 4-fold higher affinity ({K}-{D} = 3 x 10(-8) {M}) than {SH}a. {T}he amphipathic a-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. {I}nterestingly, cellular events, such as mitochondrial membrane depolarization or {DNA} fragmentation, were observed in {L}. infantum promastigotes after exposure to {SH}a and [{K}-3] {SH}a at concentrations above {IC}50. {O}ur results indicate that these temporins exert leishmanicidal activity via a primary membranolytic mechanism but can also trigger apoptotis-like death. {T}he many assets demonstrated for [{K}-3] {SH}a make this small analog an attractive template to develop new antibacterial/antiparasitic drugs.},
  keywords = {},
  booktitle = {},
  journal = {{P}los {O}ne},
  volume = {12},
  numero = {3},
  pages = {e0174024 [41 p.]},
  ISSN = {1932-6203},
  year = {2017},
  DOI = {10.1371/journal.pone.0174024},
  URL = {https://www.documentation.ird.fr/hor/fdi:010069469},
}