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Fast killing kinetics, significant therapeutic index, and high stability of melittin-derived antimicrobial peptide

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Abstract

The emergence of multidrug-resistant (MDR) bacteria is a major challenge for antimicrobial chemotherapy. Concerning this issue, antimicrobial peptides (AMPs) have been presented as novel promising antibiotics. Our previous de novo designed melittin-derived peptides (MDP1 and MDP2) indicated their potential as peptide drug leads. Accordingly, this study was aimed to evaluate the kinetics of activity, toxicity, and stability of MDP1 and MDP2 as well as determination of their structures. The killing kinetics of MDP1 and MDP2 demonstrate that all bacterial strains were rapidly killed. MDP1 and MDP2 were ca. 100- and 26.6-fold less hemolytic than melittin and found to be respectively 72.9- and 41.6-fold less cytotoxic than melittin on the HEK293 cell line. MDP1 and MDP2 showed 252- and 132-fold improvement in their therapeutic index in comparison to melittin. MDP1 and MDP2 sustained their activities in the presence of human plasma and were found to be ca. four to eightfold more stable than melittin. Spectropolarimetry analysis of MDP1 and MDP2 indicates that the peptides adopt an alpha-helical structure predominantly. According to the fast killing kinetics, significant therapeutic index, and high stability of MDP1, it could be considered as a drug lead in a mouse model of septicemia infections.

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Funding

This investigation supported by Shahid Beheshti University of medical science and Pasteur Institute of Iran. The peptides were founded by Jean-Marc Sabatier.

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Authors and Affiliations

  1. Department of Microbiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, West Azerbaijan, Iran

    Reza Akbari

  2. Department of Microbiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mojdeh Hakemi Vala

  3. Institute of NeuroPhysiopathology (INP), Faculté de Pharmacie, Université D’Aix-Marseille, UMR 7051, 27 Bd Jean Moulin, CEDEX 05, 13385, Marseille, France

    Jean-Marc Sabatier

  4. Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

    Kamran Pooshang Bagheri

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  1. Reza Akbari
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  2. Mojdeh Hakemi Vala
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  3. Jean-Marc Sabatier
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  4. Kamran Pooshang Bagheri
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Contributions

RA contributed to investigation, methodology, visualization, writing—original draft, data curation, formal analysis. MHV contributed to resources, review and editing. J-MS contributed to resources, review and editing. KPB contributed to conceptualization, methodology, data curation, formal analysis, writing—review and editing.

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Correspondence to Mojdeh Hakemi Vala or Kamran Pooshang Bagheri.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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This study did not involve human participants or animals and thus ethical approval and informed consent were not required.

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Akbari, R., Hakemi Vala, M., Sabatier, JM. et al. Fast killing kinetics, significant therapeutic index, and high stability of melittin-derived antimicrobial peptide. Amino Acids 54, 1275–1285 (2022). https://doi.org/10.1007/s00726-022-03180-2

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