Antimicrobial Activity and Toxicity of Analogs of Wasp Venom EMP Peptides. Potential Influence of Oxidized Methionine

Abstract

The antibiotic and toxic properties for four synthetic analogs of eumenine mastoparan peptides (EMP) have been tested. These properties were compared to two natural peptides found in the venom of solitary wasps Anterhynchium flavomarginatum micado (natural peptide EMP-AF) and Eumenes rubrofemoratus (natural peptide EMP-ER), respectively. Only EMP-AF-OR showed concentration-dependent growth inhibition against all bacterial species tested. Gram positive species had MIC values of 10 μg/mL for B. subtilis and 25 μg/mL for S. aureus. Gram negative species had MIC values of 25 μg/mL for E. coli and 200 μg/mL for P. aeruginosa. Of the other tested peptides, EMP-ER-D2K2 also showed activity and inhibited growth of Bacillus subtilis in a concentration-dependent manner at 200 μg/mL. Peptide EMP-ER-OR reduced the final density of Escherichia coli and B. subtilis cultures but did not impact their growth kinetics. Peptides EMP-AF-OR, EMP-ER-OR, and EMP-ER-D2K2 showed limited antifungal activity against Candida albicans or Histoplasma capsulatum. The hemolytic activity of the analogs were moderated though reports of the natural peptides, especially EMP-AF-OR, already showed low toxicity against erythrocytes. These results are discussed in the context of the potential influence of oxidized methionine on EMP activity.

Structure–Activity Relationship of New Chimeric Analogs of Mastoparan from the Wasp Venom Paravespula lewisii

“…One of the most promising groups of AMPs are peptides belonging to the mastoparan family [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mastoparan (MP) is amphiphilic α-helical tetradecapeptide with an amidated C -terminus (INLKALAALAKKIL- NH 2 ), originally isolated from the venom of the wasp Paravespula lewisii [ 10 , 11 , 19 , 20 , 22 , 24 ].…”

“…One of the most promising groups of AMPs are peptides belonging to the mastoparan family [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mastoparan (MP) is amphiphilic α-helical tetradecapeptide with an amidated C -terminus (INLKALAALAKKIL- NH 2 ), originally isolated from the venom of the wasp Paravespula lewisii [ 10 , 11 , 19 , 20 , 22 , 24 ]. Some MP analogs (tetradecapeptides with different amino acids sequences) have also been isolated from the venom of hornets, yellow jackets, and paper or solitary wasps [ 11 , 12 , 13 , 17 , 20 ].…”

“…Mastoparan (MP) is amphiphilic α-helical tetradecapeptide with an amidated C -terminus (INLKALAALAKKIL- NH 2 ), originally isolated from the venom of the wasp Paravespula lewisii [ 10 , 11 , 19 , 20 , 22 , 24 ]. Some MP analogs (tetradecapeptides with different amino acids sequences) have also been isolated from the venom of hornets, yellow jackets, and paper or solitary wasps [ 11 , 12 , 13 , 17 , 20 ]. They all are rich in hydrophobic amino acids such as Leu, Ile, and Ala, and commonly possess Lys residues.…”

“…In addition, several studies have demonstrated the antitumor and antiviral activity of MP and its analogs in vitro [ 10 , 13 , 21 ]. Although mastoparan appears to be toxic, studies have shown that its analogs have a potential therapeutic applications as antimicrobial, antiviral and antitumor agents (presumably because of their toxicity) [ 11 , 21 ]. MP as a component of cell-penetrating peptides (CPPs) has a potential pharmaceutical application in the delivery of different molecules (such as plasmids, DNA, siRNA, PNA, proteins, peptides and low-molecular-weight drugs) into cells without damaging them [ 18 , 21 , 22 , 27 , 28 , 29 , 30 ].…”

“…Therefore, several strategies to reduce the toxic side effects of AMPs and improve their antimicrobial activities have been proposed, including modification of peptide charge, alteration of the sequence length, replacement of amino acids with D-isomers or unnatural structures, modulation of peptide hydrophobicity, modification of N -and C -terminus, or alteration of the α–helical structure content [ 2 , 3 , 5 , 9 , 10 , 15 , 17 , 21 , 25 ]. So far, many mastoparan analogs have been synthesized, and although some of them contain a mastoparan sequence in their primary structure, they have lost some of the properties of MP [ 10 , 11 , 14 , 15 , 18 , 19 , 22 , 23 , 24 , 25 , 26 ].…”