Vol. 55, Issue 1, 27-56, March 2003

Mechanisms of Antimicrobial Peptide Action and Resistance

Michael R. Yeaman and Nannette Y. Yount

Division of Infectious Diseases, Harbor-University of California Los Angeles (UCLA) Medical Center; St. John's Cardiovascular Research Center, Harbor-UCLA Research and Education Institute, Torrance, California; and UCLA School of Medicine, Los Angeles, California

I. Introduction
II. Mechanisms of Antimicrobial Peptide Target Specificity and Selective Toxicity
    A. Comparative Membrane Architecture and Energy
        1. Membrane Composition, Hydrophobicity, and Charge.
        2. Membrane Asymmetry.
        3. Microbial Ligands for Antimicrobial Peptides.
        4. Transmembrane Potential.
    B. Antimicrobial Peptide Structure-Based Selective Toxicity
    C. In Vivo Preferential Affinity for Microorganisms versus Mammalian Cells
    D. Antimicrobial Peptide Localization to Restrict Exposure of Vulnerable Host Tissues
    E. Themes in Target Affinity and Selective Toxicity of Antimicrobial Peptides
III. Mechanisms of Antimicrobial Peptide Action
    A. Structural Determinants of Antimicrobial Peptide Activity
        1. Conformation ().
        2. Charge (Q).
        3. Amphipathicity (A) and Hydrophobic Moment (M_H).
        4. Hydrophobicity (H).
        5. Polar Angle ().
    B. Common Themes in Structural Determinants of Antimicrobial Peptides
    C. Initial Peptide Interactions with Membrane Targets
        1. Electrostatic Interactions.
        2. Receptor-Mediated Membrane Interactions.
    D. Events Subsequent to Initial Membrane Binding
        1. Threshold Concentration.
        2. Conformational Phase Transition.
        3. Self-Association and Multimerization.
        4. The Barrel-Stave Mechanism.
        5. The Toroid Pore or Wormhole Mechanism.
        6. The Carpet Mechanism.
    E. Mechanisms of Cell Death
        1. Membrane Dysfunction.
        2. Inhibition of Extracellular Biopolymer Synthesis.
        3. Inhibition of Intracellular Functions.
    F. Synergy among Antimicrobial Peptides
    G. Themes in Mechanisms of Action of Antimicrobial Peptides
IV. Mechanisms of Antimicrobial Peptide Resistance
    A. Constitutive and Inducible Resistance
    B. Constitutive (Passive) Resistance
        1. Inherent Mechanisms of Resistance to Antimicrobial Peptides.
        2. Altered Membrane Energetics.
        3. Electrostatic Shielding.
        4. Niche-Specific Resistance.
    C. Inducible (Adaptive) Resistance
        1. Coordinate Microbial Responses to Antimicrobial Peptide Stress.
        2. Adaptive Mechanisms of Resistance to Antimicrobial Peptides.
        3. Proteases and Peptidases.
        4. Extracellular Structural Modifications.
        5. Resistance Modifications of the Cytoplasmic Membrane.
        6. Efflux-Dependent Resistance Mechanisms.
        7. Modification of Intracellular Targets.
V. Prospectus: Therapeutic Targets of Antimicrobial Peptides
    A. Reconstitution or Potentiation of Conventional Antibiotic Efficacy
    B. Unique and Specific Microbial Targets
    C. Targeting Strategic Microbial Response Pathways
    D. Engineering New Anti-Infectives Based on Peptide Structure and Function
VI. Summary
Acknowledgments
References

Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are observed among peptides of widely diverse source and composition. Biochemical distinctions among the peptides themselves, target versus host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.