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Amino Acids

, Volume 46, Issue 9, pp 2259–2269 | Cite as

Poly-lysine peptidomimetics having potent antimicrobial activity without hemolytic activity

  • Mija Ahn
  • Binu Jacob
  • Pethaiah Gunasekaran
  • Ravichandran N. Murugan
  • Eun Kyoung Ryu
  • Ga-hyang Lee
  • Jae-Kyung Hyun
  • Chaejoon Cheong
  • Nam-Hyung Kim
  • Song Yub ShinEmail author
  • Jeong Kyu BangEmail author
Original Article

Abstract

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.

Keywords

Short peptidomimetics Antimicrobial activity Hemolytic activity Structure–activity relationship (SAR) study Poly-Lys peptidomimetics 

Abbreviations

AMPs

Antimicrobial peptides

TFA

Trifluoroacetic acid

DiSC35

3,3′-Dipropylthiadicarbocyanine iodide

ONPG

O-nitrophenyl-β-galactoside

MALDI-TOF MS

Matrix-assisted laser-desorption ionization time-of-flight mass spectrometry

RP-HPLC

Reverse-phase high-performance liquid chromatography

CFU

Colony-forming unit

MIC

Minimal inhibitory concentration

LUVs

Large unilamellar vesicles

MRSA

Methicillin-resistant Staphylococcus aureus

Notes

Acknowledgments

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.

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Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Mija Ahn
    • 1
  • Binu Jacob
    • 2
    • 6
  • Pethaiah Gunasekaran
    • 3
  • Ravichandran N. Murugan
    • 1
  • Eun Kyoung Ryu
    • 1
  • Ga-hyang Lee
    • 4
  • Jae-Kyung Hyun
    • 5
  • Chaejoon Cheong
    • 1
  • Nam-Hyung Kim
    • 3
  • Song Yub Shin
    • 2
    • 6
    Email author
  • Jeong Kyu Bang
    • 1
    Email author
  1. 1.Division of Magnetic ResonanceKorea Basic Science InstituteOchangRepublic of Korea
  2. 2.Department of Bio-Materials, Graduate SchoolChosun UniversityGwangjuRepublic of Korea
  3. 3.Molecular Embryology Laboratory, Department of Animal SciencesChungbuk National UniversityCheongjuRepublic of Korea
  4. 4.College of PharmacyChungbuk National UniversityCheongjuRepublic of Korea
  5. 5.Division of Electron Microscopic ResearchKorea Basic Science InstituteDaejeonRepublic of Korea
  6. 6.Department of Cellular and Molecular Medicine, School of MedicineChosun UniversityGwangjuRepublic of Korea

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