Structure-Activity Relationships of Antibacterial Acyl-Lysine Oligomers

Inna S. Radzishevsky; Tchelet Kovachi; Yaara Porat; Lior Ziserman; Fadia Zaknoon; Dganit Danino; Amram Mor

doi:10.1016/j.chembiol.2008.03.006

Structure-Activity Relationships of Antibacterial Acyl-Lysine Oligomers

Inna S. Radzishevsky, Tchelet Kovachi, Yaara Porat, Lior Ziserman, Fadia Zaknoon, Dganit Danino, Amram Mor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin down the importance of hydrophobicity (H) and charge (Q). Based on results obtained with OAKs displaying minimal inhibitory concentration ≤ 3 μM, the data indicate that potent inhibitory activity of the gram-negative Escherichia coli and the gram-positive Staphylococcus aureus required a relatively narrow yet distinct window of HQ values where the acyl length played multiple and critical roles, both in molecular organization and in selective activity. Thus, incorporation of long-but not short-acyl chains within a peptide backbone is shown to lead to rigid supramolecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations, including introduction of a tandem lysine motif into the oligomer backbone, enabled disassembly of aggregated OAKs and subsequently revealed tiny, nonhemolytic, yet potent antibacterial derivatives.

Original language	English
Pages (from-to)	354-362
Number of pages	9
Journal	Chemistry and Biology
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.chembiol.2008.03.006
State	Published - 21 Apr 2008
Externally published	Yes

Keywords

CHEMBIO

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10.1016/j.chembiol.2008.03.006

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title = "Structure-Activity Relationships of Antibacterial Acyl-Lysine Oligomers",

abstract = "We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin down the importance of hydrophobicity (H) and charge (Q). Based on results obtained with OAKs displaying minimal inhibitory concentration ≤ 3 μM, the data indicate that potent inhibitory activity of the gram-negative Escherichia coli and the gram-positive Staphylococcus aureus required a relatively narrow yet distinct window of HQ values where the acyl length played multiple and critical roles, both in molecular organization and in selective activity. Thus, incorporation of long-but not short-acyl chains within a peptide backbone is shown to lead to rigid supramolecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations, including introduction of a tandem lysine motif into the oligomer backbone, enabled disassembly of aggregated OAKs and subsequently revealed tiny, nonhemolytic, yet potent antibacterial derivatives.",

keywords = "CHEMBIO",

author = "Radzishevsky, {Inna S.} and Tchelet Kovachi and Yaara Porat and Lior Ziserman and Fadia Zaknoon and Dganit Danino and Amram Mor",

note = "Funding Information: This work was supported by the Israel Science Foundation (grant 387/03) and BioLineRx (grant 2006992). A.M. and I.S.R. are coinventors on patents covering the OAKs assigned to the Technion—Israel Institute of Technology and licensed to BioLineRX, a drug development company. ",

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doi = "10.1016/j.chembiol.2008.03.006",

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AU - Radzishevsky, Inna S.

AU - Kovachi, Tchelet

AU - Porat, Yaara

AU - Ziserman, Lior

AU - Zaknoon, Fadia

AU - Danino, Dganit

AU - Mor, Amram

N1 - Funding Information: This work was supported by the Israel Science Foundation (grant 387/03) and BioLineRx (grant 2006992). A.M. and I.S.R. are coinventors on patents covering the OAKs assigned to the Technion—Israel Institute of Technology and licensed to BioLineRX, a drug development company.

PY - 2008/4/21

Y1 - 2008/4/21

N2 - We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin down the importance of hydrophobicity (H) and charge (Q). Based on results obtained with OAKs displaying minimal inhibitory concentration ≤ 3 μM, the data indicate that potent inhibitory activity of the gram-negative Escherichia coli and the gram-positive Staphylococcus aureus required a relatively narrow yet distinct window of HQ values where the acyl length played multiple and critical roles, both in molecular organization and in selective activity. Thus, incorporation of long-but not short-acyl chains within a peptide backbone is shown to lead to rigid supramolecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations, including introduction of a tandem lysine motif into the oligomer backbone, enabled disassembly of aggregated OAKs and subsequently revealed tiny, nonhemolytic, yet potent antibacterial derivatives.

AB - We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin down the importance of hydrophobicity (H) and charge (Q). Based on results obtained with OAKs displaying minimal inhibitory concentration ≤ 3 μM, the data indicate that potent inhibitory activity of the gram-negative Escherichia coli and the gram-positive Staphylococcus aureus required a relatively narrow yet distinct window of HQ values where the acyl length played multiple and critical roles, both in molecular organization and in selective activity. Thus, incorporation of long-but not short-acyl chains within a peptide backbone is shown to lead to rigid supramolecular organization responsible for poor antibacterial activity and enhanced hemolytic activity. However, sequence manipulations, including introduction of a tandem lysine motif into the oligomer backbone, enabled disassembly of aggregated OAKs and subsequently revealed tiny, nonhemolytic, yet potent antibacterial derivatives.

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DO - 10.1016/j.chembiol.2008.03.006

M3 - 文章

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AN - SCOPUS:41949084916

SN - 2451-9448

VL - 15

SP - 354

EP - 362

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 4

ER -

Structure-Activity Relationships of Antibacterial Acyl-Lysine Oligomers

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