Selective amino acid substitution reduces cytotoxicity of the antimicrobial peptide mastoparan

Biochim Biophys Acta. 2016 Nov;1858(11):2699-2708. doi: 10.1016/j.bbamem.2016.07.001. Epub 2016 Jul 14.


The emergence of antibiotic-resistant clinical isolates and the decreased rate of development of new antibiotics are a constant threat to human health. In this context, the therapeutic value of mastoparan (MP), a toxin from wasp venom, has been extensively studied. However, since MP shows significant cytotoxic activities, further optimization is needed. Here we evaluated the antimicrobial and cytolytic activities of an MP analog created by Ala-substitution in positions 5 and 8, named [I5, R8] mastoparan ([I5, R8] MP). We found that [I5, R8] MP displayed a broad-spectrum antimicrobial activity against bacteria and fungi (MIC in the range 3-25μM), without being hemolytic or cytotoxic toward HEK-293 cells. In addition, [I5, R8] MP-amide was highly potent (MIC=3μM) against antibiotic-resistant bacteria. The interaction with microbial membranes was investigated revealing that [I5, R8] MP is able to form an active amphipathic α-helix conformation and to disturb membranes causing lysis and cell death. Based on our findings, we hypothesize that [I5, R8] MP follows a mechanism of action similar to that proposed for MP, where the pore-forming activity leads to cell death. Our results indicate that hydrophobic moment modified by amino acid substitution may enhance MP selectivity.

Keywords: Antimicrobial peptides; Hydrophobic moment; Mastoparan; Membrane permeabilization/depolarization; Rational design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Acinetobacter baumannii / growth & development
  • Amino Acid Substitution*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Candida albicans / drug effects
  • Candida albicans / growth & development
  • Enterococcus faecalis / drug effects
  • Enterococcus faecalis / growth & development
  • Erythrocytes / cytology
  • Erythrocytes / drug effects
  • Escherichia coli / drug effects
  • Escherichia coli / growth & development
  • HEK293 Cells
  • Hemolysis / drug effects
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Intercellular Signaling Peptides and Proteins
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / growth & development
  • Listeria / drug effects
  • Listeria / growth & development
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / growth & development
  • Microbial Sensitivity Tests
  • Peptides / chemical synthesis
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Structure, Secondary
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / growth & development
  • Species Specificity
  • Streptococcus pyogenes / drug effects
  • Streptococcus pyogenes / growth & development
  • Structure-Activity Relationship
  • Wasp Venoms / chemical synthesis
  • Wasp Venoms / metabolism
  • Wasp Venoms / pharmacology*


  • Anti-Bacterial Agents
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Wasp Venoms
  • mastoparan