Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids

Yang, L; Gordon, V D; Trinkle, D R; Schmidt, N W; Davis, M A; DeVries, C; Som, A; Cronan, Jr, J E; Tew, G N; Wong, G C.L.

Title: Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids

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Abstract

Phenylene ethynylenes comprise a prototypical class of synthetic antimicrobial compounds that mimic antimicrobial peptides produced by eukaryotes and have broad-spectrum antimicrobial activity. We show unambiguously that bacterial membrane permeation by these antimicrobials depends on the presence of negative intrinsic curvature lipids, such as phosphatidylethanolamine (PE) lipids, found in high concentrations within bacterial membranes. Plate-killing assays indicate that a PE-knockout mutant strain of Escherichia coli drastically out-survives the wild type against the membrane-active phenylene ethynylene antimicrobials, whereas the opposite is true when challenged with traditional metabolic antibiotics. That the PE deletion is a lethal mutation in normative environments suggests that resistant bacterial strains do not evolve because a lethal mutation is required to gain immunity. PE lipids allow efficient generation of negative curvature required for the circumferential barrel of an induced membrane pore; an inverted hexagonal HII phase, which consists of arrays of water channels, is induced by a small number of antimicrobial molecules. The estimated antimicrobial occupation in these water channels is nonlinear and jumps from {approx}1 to 3 per 4 nm of induced water channel length as the global antimicrobial concentration is increased. By comparing to exactly solvable 1D spin models for magnetic systems, we quantify the cooperativity ofmore » these antimicrobials.« less

Authors:: Yang, L; Gordon, V D; Trinkle, D R; Schmidt, N W; Davis, M A; DeVries, C; Som, A; Cronan, Jr, J E; Tew, G N; Wong, G C.L.

Publication Date:: Thu May 28 00:00:00 EDT 2009

Research Org.:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 953515

Report Number(s):: SLAC-REPRINT-2009-368
Journal ID: ISSN 0027-8424; PNASA6; TRN: US201002%%1343

DOE Contract Number:: AC02-76SF00515

Resource Type:: Journal Article

Journal Name:: Proc. Nat. Acad. Sci. 105:20595,2008

Additional Journal Information:: Journal Volume: 105; Journal Issue: 52; Journal ID: ISSN 0027-8424

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ANTIBIOTICS; ESCHERICHIA COLI; IMMUNITY; INTERACTIONS; LETHAL MUTATIONS; LIPIDS; MEMBRANE PORES; MEMBRANES; MOLECULES; MUTANTS; PEPTIDES; WATER; Other,OTHER, CHEM

Citation Formats


                    Yang, L, Gordon, V D, Trinkle, D R, Schmidt, N W, Davis, M A, DeVries, C, Som, A, Cronan, Jr, J E, Tew, G N, and Wong, G C.L. Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids.  United States: N. p., 2009. 
        Web.

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                    Yang, L, Gordon, V D, Trinkle, D R, Schmidt, N W, Davis, M A, DeVries, C, Som, A, Cronan, Jr, J E, Tew, G N, & Wong, G C.L. Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids.  United States.

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                    Yang, L, Gordon, V D, Trinkle, D R, Schmidt, N W, Davis, M A, DeVries, C, Som, A, Cronan, Jr, J E, Tew, G N, and Wong, G C.L. 2009.  
        "Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids".  United States.

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@article{osti_953515,

  title        = {Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids},

  author       = {Yang, L and Gordon, V D and Trinkle, D R and Schmidt, N W and Davis, M A and DeVries, C and Som, A and Cronan, Jr, J E and Tew, G N and Wong, G C.L.},

  abstractNote = {Phenylene ethynylenes comprise a prototypical class of synthetic antimicrobial compounds that mimic antimicrobial peptides produced by eukaryotes and have broad-spectrum antimicrobial activity. We show unambiguously that bacterial membrane permeation by these antimicrobials depends on the presence of negative intrinsic curvature lipids, such as phosphatidylethanolamine (PE) lipids, found in high concentrations within bacterial membranes. Plate-killing assays indicate that a PE-knockout mutant strain of Escherichia coli drastically out-survives the wild type against the membrane-active phenylene ethynylene antimicrobials, whereas the opposite is true when challenged with traditional metabolic antibiotics. That the PE deletion is a lethal mutation in normative environments suggests that resistant bacterial strains do not evolve because a lethal mutation is required to gain immunity. PE lipids allow efficient generation of negative curvature required for the circumferential barrel of an induced membrane pore; an inverted hexagonal HII phase, which consists of arrays of water channels, is induced by a small number of antimicrobial molecules. The estimated antimicrobial occupation in these water channels is nonlinear and jumps from {approx}1 to 3 per 4 nm of induced water channel length as the global antimicrobial concentration is increased. By comparing to exactly solvable 1D spin models for magnetic systems, we quantify the cooperativity of these antimicrobials.},

  doi          = {},

  url          = {https://www.osti.gov/biblio/953515},
  journal      = {Proc. Nat. Acad. Sci. 105:20595,2008},

  issn         = {0027-8424},

  number       = 52,

  volume       = 105,

  place        = {United States},

  year         = {Thu May 28 00:00:00 EDT 2009},

  month        = {Thu May 28 00:00:00 EDT 2009}

}

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