Historical perspectiveThe interaction of antimicrobial peptides with membranes
Graphical abstract
Introduction
Antimicrobial peptides (AMPs), also called host defense peptides [1], are an evolutionarily conserved component of the innate immune response system and are found in every organism [2], [3], [4], [5], [6]. They are essential components of the host defense against infections. Such peptides display remarkable activity against bacteria, fungi, viruses and parasites [7], [8]. They are also involved in immunomodulatory activities and inflammatory processes [9], [10], [11]. Additionally, there is a certain degree of coupling between the innate and adaptive immune systems: antimicrobial peptides influence both, the quality and effectivity of immune and inflammatory responses [12].
The discovery of AMPs goes back to 1939 [13], [14], [15] when gramicidin was discovered. The first reported animal-originated AMP is defensin, which was isolated from rabbit leukocytes [16].
The target of AMPs is the membrane. AMPs are thought to overcome the resistance problem of traditional antibiotics (‘the antibiotic crisis’ [17]). It was argued that a resistance against AMPs could only be attained by a change of the lipid composition (different charge, changed fluidity). But this idea is too simple and unfortunately not true. Alterations of net surface charges, structural alterations in LPS, changes in the membrane proteins, increased production of proteolytic enzymes or glycocalyx shielding can inactivate AMPs [7], [8], [18]. A prospective resistance against AMPs in a broad medical use can never be excluded [19], but the structure-activity-relationship of natural AMPs should serve more as a template for the design of new peptides.
Besides that, antimicrobial peptides can also be involved in biochemical processes like the inactivation of nucleic acids and cytoplasmic proteins [18]. Many AMPs are active against cancer cells [5], [20], [21], [22], [23]. For example melittin (from the bee venom) inhibits tumor cell metastasis by reducing cell motility and migration [24]. The NK-2 (derivative from the porcine NK-lysin) killing activity correlates with the membrane exposure of negatively charged PS on the surface of cancer cells [21]. Magainin II (from frog skin) inhibited cell proliferation of bladder cancer cells in a dose-dependent manner [25], gomesin (from the spider Acanthoscurria gomesiana) significantly delayed subcutaneous murine melanoma development and increased the number of living treated animals with tumors below the allowed maximal size limit [26].
It is still unclear why some AMPs kill cancer cells but others do not [27]. Beside the effect of opposite charges of the peptides and the membrane, differences in the fluidity and/or morphological changes of the membrane could be involved, as well as increased levels of sialic acid of glycolipids [20]. Obviously, the interplay between the peptide and membrane-based factors is of utmost importance [22], and this shall be explained in this review by means of some examples. We will show that physical-chemical studies of the membrane water interface can provide valuable information to understand and to control peptide function. We will do this by first describing the general questions and then concentrate on a few specific systems to demonstrate the power of recent methodical developments in interfacial science.
Section snippets
Mode of action
The modes of action by which antimicrobial peptides kill bacteria include disrupting membranes, interfering with metabolism, and targeting cytoplasmic components.
> 5000 AMPs are identified and published in databases [28], [29], [30], but their mode of action is still not well understood [18], [31], [32]. As an example, the cationic, amphipathic, and alpha-helical peptides are typically 12–37 amino acid residues in length, and may have a kink or a central hinge region [8]. But their sequence and
Interactions with membrane models
Nowadays antimicrobial peptides (AMPs) are in the center of research in many fields of natural sciences. Due to their unique mode of action (rapid, irreversible and non-cytotoxic for mammalian cells) [68], AMPs are becoming more and more interesting for medical applications. New and effective drugs [69], based on the structural diversity of AMPs, are in the focus of many studies. Thus, the task for physical chemists is the basic study of AMPs using simple models to elucidate special peptide
Circular dichroism spectroscopy (CD)
CD was used for the determination of the peptide secondary structure elements in bulk. CD spectra of the studied solutions were recorded on a Jasco J-715 (Japan) spectrometer in the wavelength interval from 180 to 300 nm with 0.2 nm step resolution using quartz cuvettes with an optical path length of 0.1 cm. The signal-to-noise ratio was improved by accumulating 10 scans. For all experiments, the peptide concentration was kept constant (0.2 mg/ml) and the measurements were performed at 20 °C. Data
Interaction with differently charged surfactants
Surfactants as sodium dodecylsulfate (SDS) aggregate in solution above the critical micelle concentration (cmc). Depending on the chemical structure and the resulting forces, micelles can exhibit different shapes (mostly spherical, but also oblate ellipsoids and cylindrical micelles have been observed [101]). The hydrophilic head group region is in contact with the surrounding water or buffer and the hydrophobic tail region is in the center of the micelle and shielded from interaction with
Alternative strategies
Alternative strategies and new molecules for antimicrobial treatment are a major focus of synthetic and pharmaceutical chemistry. AMPs are a major class of membrane-active peptides (MAPs) which strongly interact with negatively charged microbial surfaces leading to perturbation and disruption of membranes. However, despite intense research efforts aimed at developing AMPs as therapeutic agents, limited clinical outcome has resulted so far [113], [114]. A major disadvantage of natural AMPs is
Acknowledgement
The authors thank Prof. Jörg Andrä (Hamburg University of Applied Sciences, Department Biotechnologie) for providing the arenicins and discussions, as well as HASYLAB at DESY, Hamburg, Germany, for beamtime and support. We profited from the close interaction with many gifted graduate students and postdocs, for the studies of peptides at membranes predominantly with Claudia Olak, Claudia Dannehl, Maria Hoernke, and Janos Keller.
References (131)
- et al.
Cationic host defense (antimicrobial) peptides
Curr Opin Immunol
(2006) - et al.
Biotechnological potential of antimicrobial peptides from flowers
Peptides
(2008) - et al.
Role of lipids in the interaction of antimicrobial peptides with membranes
Prog Lipid Res
(2012) - et al.
The role of cationic antimicrobial peptides in innate host defences
Trends Microbiol
(2000) - et al.
Amped up immunity: how antimicrobial peptides have multiple roles in immune defense
Trends Immunol
(2009) - et al.
Fractionation of the bactericidal agent from cultures of a soil Bacillus
J Biol Chem
(1940) - et al.
Membrane-active host defense peptides - challenges and perspectives for the development of novel anticancer drugs
Chem Phys Lipids
(2011) - et al.
The Nk-lysin derived peptide Nk-2 preferentially kills cancer cells with increased surface levels of negatively charged phosphatidylserine
FEBS Lett
(2005) - et al.
Studies on anticancer activities of antimicrobial peptides
Biochim Biophys Acta Biomembr
(2008) - et al.
Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines
Eur Urol
(2006)
Effective topical treatment of subcutaneous murine B16f10-Nex2 melanoma by the antimicrobial peptide gomesin
Neoplasia
Cationic amphiphilic peptides with cancer-selective toxicity
Eur J Pharmacol
Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides
Biochim Biophys Acta
Structure, location, and lipid perturbations of melittin at the membrane interface
Biophys J
The membrane interactions of antimicrobial peptides revealed by solid-state NMR spectroscopy
Chem Phys Lipids
Selective cytotoxicity of dermaseptin S3 toward intraerythrocytic plasmodium falciparum and the underlying molecular basis
J Biol Chem
Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes?
Peptides
Intrinsic fluorescence study of lipid-protein interactions in membrane models. Binding of melittin, an amphipathic peptide, to phospholipid vesicles
Biochim Biophys Acta
Differential scanning calorimetry and X-ray diffraction studies of the specificity of the interaction of antimicrobial peptides with membrane-mimetic systems
Biochim Biophys Acta Biomembr
An anionic antimicrobial peptide from toad Bombina maxima
Biochem Biophys Res Commun
Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and haemolytic activity of amphipathic helical peptides
FEBS Lett
Optimization of the antimicrobial activity of magainin peptides by modification of charge
FEBS Lett
Peptide-lipid interactions of the β-hairpin antimicrobial peptide tachyplesin and its linear derivatives from solid-state NMR
Biochim Biophys Acta
Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure
J Biol Chem
Folding amphipathic helices into membranes: amphiphilicity trumps hydrophobicity
J Mol Biol
Design of novel analogue peptides with potent antibiotic activity based on the antimicrobial peptide, hp (2 − 20), derived from n-terminus of Helicobacter pylori ribosomal protein L1
Biochim Biophys Acta
Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action
Biochim Biophys Acta
Detergent-like actions of linear amphipathic cationic antimicrobial peptides
Biochim Biophys Acta Biomembr
Langmuir monolayers to study interactions at model membrane surfaces
Adv Colloid Interf Sci
Langmuir monolayers as models to study processes at membrane surfaces
Adv Colloid Interf Sci
Grazing incidence X-ray diffraction studies of condensed double-chain phospholipid monolayers formed at the soft air/water interface
Adv Colloid Interf Sci
X-ray investigation of monolayers formed at the soft air/water interface
Curr Opin Colloid Interface Sci
Purification and primary structure of two isoforms of arenicin, a novel antimicrobial peptide from marine polychaeta Arenicola marina
FEBS Lett
The antimicrobial peptide arenicin-1 promotes generation of reactive oxygen species and induction of apoptosis
Biochim Biophys Acta
Synergistic effect of antimicrobial peptide arenicin-1 in combination with antibiotics against pathogenic bacteria
Res Microbiol
Analysis of neutron and X-ray reflectivity data by constrained least-squares methods
Physica B
Recombinant expression, synthesis, purification, and solution structure of arenicin
Biochem Biophys Res Commun
Antimicrobial peptides: natural templates for synthetic membrane-active compounds
Cell Mol Life Sci
Antimicrobial peptides of multicellular organisms
Nature
Antimicrobial peptides with cell-penetrating peptide properties and vice versa
Eur Biophys J
Antimicrobial peptides
Pharmaceuticals
Animal antimicrobial peptides: an overview
Biopolymers
Peptide antibiotics and their role in innate immunity
Annu Rev Immunol
Modulation of the activity of secretory phospholipase A2 by antimicrobial peptides
Antimicrob Agents Chemother
Studies on a bactericidal agent extracted from a soil bacillus: I. Preparation of the agent. Its activity in vitro
J Exp Med
Studies on a bactericidal agent extracted from a soil bacillus: II. Protective effect of the bactericidal agent against experimental Pneumococcus infections in mice
J Exp Med
Phagocytin: a bactericidal substance from polymorphonuclear leucocytes
J Exp Med
Antibiotics: a shot in the arm
Nature
Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?
Nat Rev Microbiol
Arming the enemy: the evolution of resistance to self-proteins
Microbiology
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