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Poly-lysine peptidomimetics having potent antimicrobial activity without hemolytic activity

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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.

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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

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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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Authors and Affiliations

  1. Division of Magnetic Resonance, Korea Basic Science Institute, 804-1 Yangchung-ri, Ochang, Chungbuk, 363-883, Republic of Korea

    Mija Ahn, Ravichandran N. Murugan, Eun Kyoung Ryu, Chaejoon Cheong & Jeong Kyu Bang

  2. Department of Bio-Materials, Graduate School, Chosun University, Gwangju, 501-759, Republic of Korea

    Binu Jacob & Song Yub Shin

  3. Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea

    Pethaiah Gunasekaran & Nam-Hyung Kim

  4. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea

    Ga-hyang Lee

  5. Division of Electron Microscopic Research, Korea Basic Science Institute, 113 Gwahanno, Daejeon, 305-333, Republic of Korea

    Jae-Kyung Hyun

  6. Department of Cellular and Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea

    Binu Jacob & Song Yub Shin

Authors
  1. Mija Ahn
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  2. Binu Jacob
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  3. Pethaiah Gunasekaran
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  4. Ravichandran N. Murugan
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  5. Eun Kyoung Ryu
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  6. Ga-hyang Lee
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  7. Jae-Kyung Hyun
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  8. Chaejoon Cheong
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  9. Nam-Hyung Kim
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  10. Song Yub Shin
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  11. Jeong Kyu Bang
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Corresponding authors

Correspondence to Song Yub Shin or Jeong Kyu Bang.

Additional information

M. Ahn and B. Jacob contributed equally to this work.

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Ahn, M., Jacob, B., Gunasekaran, P. et al. Poly-lysine peptidomimetics having potent antimicrobial activity without hemolytic activity. Amino Acids 46, 2259–2269 (2014). https://doi.org/10.1007/s00726-014-1778-z

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  • DOI: https://doi.org/10.1007/s00726-014-1778-z

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