Poly-lysine peptidomimetics having potent antimicrobial activity without hemolytic activity
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Diversity of sequence and structure in naturally occurring antimicrobial peptides (AMPs) limits their intensive structure–activity relationship (SAR) study. In contrast, peptidomimetics have several advantages compared to naturally occurring peptide in terms of simple structure, convenient to analog synthesis, rapid elucidation of optimal physiochemical properties and low-cost synthesis. In search of short antimicrobial peptides using peptidomimetics, which provide facile access to identify the key factors involving in the destruction of pathogens through SAR study, a series of simple and short peptidomimetics consisting of multi-Lys residues and lipophilic moiety have been prepared and found to be active against several Gram-negative and Gram-positive bacteria containing methicillin-resistant Staphylococcus aureus (MRSA) without hemolytic activity. Based on the SAR studies, we found that hydrophobicity, +5 charges of multiple Lys residues, hydrocarbon tail lengths and cyclohexyl group were crucial for antimicrobial activity. Furthermore, membrane depolarization, dye leakage, inner membrane permeability and time-killing kinetics revealed that bacterial-killing mechanism of our peptidomimetics is different from the membrane-targeting AMPs (e. g. melittin and SMAP-29) and implied our peptidomimetics might kill bacteria via the intracellular-targeting mechanism as done by buforin-2.
KeywordsShort peptidomimetics Antimicrobial activity Hemolytic activity Structure–activity relationship (SAR) study Poly-Lys peptidomimetics
- MALDI-TOF MS
Matrix-assisted laser-desorption ionization time-of-flight mass spectrometry
Reverse-phase high-performance liquid chromatography
Minimal inhibitory concentration
Large unilamellar vesicles
Methicillin-resistant Staphylococcus aureus
This work was supported in part by Korea Basic Science Institute’s research grant T34418 (J.K.B), the Next-Generation BioGreen 21 Program (#PJ009594, N.H.K), Rural Development Administration, Republic of Korea and Korea Research Foundation funded by the Korean Government (KRF-2011-0009039 to S.Y.S.).
Conflict of interest
The authors have declared that there is no conflict of interest.
- Ahn M, Murugan RN, Jacob B, Hyun JK, Cheong C, Hwang E, Park HN, Seo JH, Srinivasrao G, Lee KS, Shin SY, Bang JK (2013) Discovery of novel histidine-derived lipo-amino acids: applied in the synthesis of ultra-short antimicrobial peptidomimetics having potent antimicrobial activity, salt resistance and protease stability. Eur J Med Chem 68:10–18PubMedCrossRefGoogle Scholar
- Bocheva A, Nocheva H, Pavlov N, Todorov P, Calmes M, Martinez J, Naydenova E (2013) Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs. Amino Acids 45:983–988Google Scholar
- Kim J-K, Lee E, Shin S, Jeong K-W, Lee J-Y, Bae S-Y, Kim S-H, Lee J, Kim S, Lee D, Hwang J-S, Kim Y (2011) Structure and function of papiliocin with antimicrobial and anti-inflammatory activities isolated from the swallowtail butterfly Papilio xuthus. J Biol Chem 286:41296–41311PubMedCentralPubMedCrossRefGoogle Scholar
- Murugan RN, Jacob B, Ahn M, Hwang E, Sohn H, Park HN, Lee E, Seo JH, Cheong C, Nam KY, Hyun JK, Jeong KW, Kim Y, Shin SY, Bang JK (2013b) De novo design and synthesis of ultra-short peptidomimetics having dual antimicrobial and anti-inflammatory activities. PLoS One 8:e80025PubMedCentralPubMedCrossRefGoogle Scholar