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Antimicrobial 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 α-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 IC 50 . 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.

Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent