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Raja Z., Andre S., Abbassi F., Humblot V., Lequin O., Bouceba T., Correia I., Casale S., Foulon T., Sereno Denis, Oury Bruno, Ladram A. (2017). Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent. Plos One, 12 (3), e0174024 [41 p.]. ISSN 1932-6203

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Lien direct chez l'éditeur doi:10.1371/journal.pone.0174024

Titre
Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent
Année de publication2017
Type de documentArticle référencé dans le Web of Science WOS:000398945800043
AuteursRaja Z., Andre S., Abbassi F., Humblot V., Lequin O., Bouceba T., Correia I., Casale S., Foulon T., Sereno Denis, Oury Bruno, Ladram A.
SourcePlos One, 2017, 12 (3), p. e0174024 [41 p.]. p. e0174024 [41 p.] ISSN 1932-6203
RésuméAntimicrobial peptides (AMPs) are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa), a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K-3] SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma), with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K-3] SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy). Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry) allowed us to detail peptide-membrane interactions. [K-3] SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (K-D = 3 x 10(-8) M) than SHa. The amphipathic a-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K-3] SHa at concentrations above IC50. Our results indicate that these temporins exert leishmanicidal activity via a primary membranolytic mechanism but can also trigger apoptotis-like death. The many assets demonstrated for [K-3] SHa make this small analog an attractive template to develop new antibacterial/antiparasitic drugs.
Plan de classementEntomologie médicale / Parasitologie / Virologie [052] ; Santé : généralités [050] ; Sciences fondamentales / Techniques d'analyse et de recherche [020]
LocalisationFonds IRD [F B010069469]
Identifiant IRDfdi:010069469
Lien permanenthttp://www.documentation.ird.fr/hor/fdi:010069469

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