Antimicrobial mechanism of pore-forming protegrin peptides: 100 pores to kill E. coli

Dan Bolintineanu, Ehsan Hazrati, H. Ted Davis, Robert I. Lehrer, Yiannis Kaznessis

    Research output: Contribution to journalArticlepeer-review

    68 Scopus citations

    Abstract

    Antimicrobial peptides (AMPs), important effector molecules of the innate immune system, also provide templates for designing novel antibiotics. Protegrin, an especially potent AMP found in porcine leukocytes, was recently shown to form octameric transmembrane pores. We have employed a combination of experiments and models spanning length scales from the atomistic to the cellular level in order to elucidate the microbicidal mechanism of protegrin. Comparison of the modeling and experimental data suggests that approximately 10-100 protegrin pores are necessary to explain the observed rates of potassium leakage and Escherichia coli death in exponential-phase bacteria. The kinetics of viability loss suggest that bacterial death results largely from uncontrolled ion exchange processes and decay of transmembrane potential. However, ion exchange processes alone cannot account for the experimentally observed cell swelling and osmotic lysis-a redundant "overkill" mechanism most likely to occur in locales with high protegrin concentrations. Although our study is limited to protegrin and E. coli, the timeline of events described herein is likely shared by other AMPs that act primarily by permeabilizing microbial membranes. This work provides many of the missing links in describing antimicrobial action, as well as providing a quantitative connection between several previous experimental and simulation studies of protegrin.

    Original languageEnglish (US)
    Pages (from-to)1-8
    Number of pages8
    JournalPeptides
    Volume31
    Issue number1
    DOIs
    StatePublished - Jan 2010

    Bibliographical note

    Funding Information:
    We thank Min Jun Lee and Lorenzo Menzel for technical assistance. This work was supported by a grant from NIH ( GM 070989 ). Computational support from the Minnesota Supercomputing Institute (MSI) is gratefully acknowledged. This work was also partially supported by National Computational Science Alliance under TG-MCA04N033 and utilized the TeraGrid Cluster.

    Copyright:
    Copyright 2010 Elsevier B.V., All rights reserved.

    Keywords

    • Antimicrobial peptides
    • Mechanism of action
    • Multiscale model

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