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Action mechanism of melittin-derived antimicrobial peptides, MDP1 and MDP2, de novo designed against multidrug resistant bacteria

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Abstract

The emergence and dissemination of multidrug resistant (MDR) bacteria are major challenges for antimicrobial chemotherapy of bacterial infections. In this critical condition, cationic antimicrobial peptides are ‘novel’ promising candidate antibiotics to overcome the issue. In this study, we investigated the antibacterial mechanism of new melittin-derived peptides (i.e., MDP1 and MDP2) against multidrug resistant Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. MDP1 was designed with deletion of three amino acid residues, i.e., S18, W19, and I20, from the end of second hydrophobic motif of melittin. In the next step, VLTTG in MDP1 sequence was substituted with tryptophan residue. MDP1 and MDP2 had a high-antibacterial activity against MDR and reference strains of S. aureus, E. coli, and P. aeruginosa. DNA and calcein release and flow cytometry assays indicate a time-dependent antibacterial activity on the examined bacteria affected by both MDP1 and MDP2. Finally, SEM analyses highlighted dose- and time-dependent effects of MDP1 and MDP2 on S. aureus and E. coli bacteria by induction of vesicle or pore formation as well as cell lysis. In this study we successfully showed that rational truncation of large hydrophobic motifs can lead to significant reduction in toxicity against human RBCs and improving the antibacterial activity as well. Analyses of data from DNA release, fluorometry, flow cytometry, and morphological assays demonstrated that the MDP1 and MDP2 altered the integrity of both Gram-positive and Gram-negative bacterial membranes and killed the bacteria via membrane damages.

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Abbreviations

MDP:

Melittin derived peptide

MDR:

Multidrug resistant

AMP:

Antimicrobial peptide

AA:

Amino acid

MW:

Molecular weight

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Acknowledgments

The authors gratefully acknowledge the financial and facility support provided by the Shahid Beheshti University of medical sciences, Pasteur Institute of Iran, and INSERM UMRs 1097, Aix-Marseille Universite.

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Authors and Affiliations

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

    Reza Akbari, Mojdeh Hakemi Vala & Ali Hashemi

  2. INSERM UMRs 1097, Parc scientifique et technologique de Luminy, Aix-Marseille Universite, Marseille, France

    Jean-Marc Sabatier

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

    Hossein Aghazadeh & Kamran Pooshang Bagheri

Authors
  1. Reza Akbari
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  2. Mojdeh Hakemi Vala
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  3. Ali Hashemi
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  4. Hossein Aghazadeh
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  5. Jean-Marc Sabatier
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  6. Kamran Pooshang Bagheri
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Contributions

RA designed the peptides, performed all experiments and analyses, and also wrote the manuscript. MHV served as supervisor and revised the manuscript. AH served as advisor. HA contributed to flow cytometry assays. JMS produced the designed peptides and contributed to the revision of manuscript. KPB supervised the project and contributed to the peptide design, experimental design, analyses, writing, revision, and redaction of the manuscript. The idea of designing melittin-derived peptides based on the reduction of hydrophobicity belongs to the corresponding author, KPB.

Corresponding authors

Correspondence to Mojdeh Hakemi Vala, Jean-Marc Sabatier or Kamran Pooshang Bagheri.

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Conflict of interests

The authors declare that they have no conflict of interest.

Research involving human and animal participants

This article does not contain studies with human participants or animals performed by any of the authors.

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Handling Editor: N. Sewald.

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Akbari, R., Hakemi Vala, M., Hashemi, A. et al. Action mechanism of melittin-derived antimicrobial peptides, MDP1 and MDP2, de novo designed against multidrug resistant bacteria. Amino Acids 50, 1231–1243 (2018). https://doi.org/10.1007/s00726-018-2596-5

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  • DOI: https://doi.org/10.1007/s00726-018-2596-5

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