Membrane-active peptides as anti-infectious agents (original) (raw)
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Biotherapeutic effect of cell-penetrating peptides against microbial agents: a review
Tissue Barriers, 2021
Selective permeability of biological membranes represents a significant barrier to the delivery of therapeutic substances into both microorganisms and mammalian cells, restricting the access of drugs into intracellular pathogens. Cell-penetrating peptides usually 5-30 amino acids with the characteristic ability to penetrate biological membranes have emerged as promising antimicrobial agents for treating infections as well as an effective delivery modality for biological conjugates such as nucleic acids, drugs, vaccines, nanoparticles, and therapeutic antibodies. However, several factors such as antimicrobial resistance and poor drug delivery of the existing medications justify the urgent need for developing a new class of antimicrobials. Herein, we review cell-penetrating peptides (CPPs) used to treat microbial infections. Although these peptides are biologically active for infections, effective transduction into membranes and cargo transport, serum stability, and half-life must be improved for optimum functions and development of next-generation antimicrobial agents.
Antimicrobial peptides: to membranes and beyond
Expert Opinion on Drug Discovery, 2009
Objective: This review will summarize findings on these alternative non-lytic modes of antimicrobial action that go beyond membrane disruption, with an emphasis on the specific interaction with microbial cell wall/membrane components, signaling of AMP exposure, and intracellular targets of peptide action. We will also explore how novel technologies can help to reveal, characterize and exploit these antimicrobial properties. Conclusion: Detailed knowledge on non-lytic modes of action of antimicrobial peptides will help in the design and discovery of novel antibacterial and antifungal compounds.
Cell-penetrating antimicrobial peptides - prospectives for targeting intracellular infections
Pharmaceutical research, 2015
To investigate the suitability of three antimicrobial peptides (AMPs) as cell-penetrating antimicrobial peptides. Cellular uptake of three AMPs (PK-12-KKP, SA-3 and TPk) and a cell-penetrating peptide (penetratin), all 5(6)-carboxytetramethylrhodamine-labeled, were tested in HeLa WT cells and analyzed by flow cytometry and confocal microscopy. Furthermore, the effects of the peptides on eukaryotic cell viability as well as their antimicrobial effect were tested. In addition, the disrupting ability of the peptides in the presence of bilayer membranes of different composition were analyzed. AMP uptake relative to penetratin was ~13% (PK-12-KKP), ~66% (SA-3) and ~50% (TPk). All four peptides displayed a punctate uptake pattern in HeLa WT cells with co-localization to lysosomes and no indication that clathrin-mediated endocytosis was the predominant uptake mechanism. TPk showed the highest antibacterial activity. SA-3 exhibited selective disruption of liposomes mimicking Gram-positive a...
Antimicrobial peptides: natural templates for synthetic membrane-active compounds
The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversified array of sequences and folds, AMPs do share a common amphiphilic 3-Darrangement.This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. This minireview reports on current understanding of the modes of interaction of AMPs with biological and model membranes, especially focusing on recent insights into the folding and oligomerization requirements of peptides to bind and insert into lipid membranes and exert their antibiotic effects. Given the potential of AMPs to be developed into a new class of anti-infective agents, emphasis is placed on how the information on peptidemembrane interactions could direct the design and selection of improved biomimetic synthetic peptides with antibiotic properties
Membrane permeabilization by multivalent anti-microbial peptides
Protein and peptide …, 2009
Antimicrobial peptides (AMP's) are promising compounds in the battle against antibiotic resistant pathogens. Many AMP's function by interacting with the bacterial membrane and selectively permeabilizing it. Improvements are desired in the potency and the in vivo stability of the AMP's. Both aspects have been approached by the preparation of multivalent versions of AMP's that contain several copies of the peptide attached to a scaffold or core molecule. Both short and long sequences have been used and in selected cases major increases in antibacterial activity, membrane permeabilization potency and in vivo stability have been obtained.
Basis for Selectivity of Cationic Antimicrobial Peptides for Bacterial Versus Mammalian Membranes
Journal of Biological Chemistry, 2005
Novel cationic antimicrobial peptides typified by structures such as KKKKKKAAXAAWAAXAA-NH 2 , where X ؍ Phe/Trp, and several of their analogues display high activity against a variety of bacteria but exhibit no hemolytic activity even at high dose levels in mammalian erythrocytes. To elucidate their mechanism of action and source of selectivity for bacterial membranes, phospholipid mixtures mimicking the compositions of natural bacterial membranes (containing anionic lipids) and mammalian membranes (containing zwitterionic lipids ؉ cholesterol) were challenged with the peptides. We found that peptides readily inserted into bacterial lipid mixtures, although no insertion was detected in model "mammalian" membranes. The depth of peptide insertion into model bacterial membranes was estimated by Trp fluorescence quenching using doxyl groups variably positioned along the phospholipid acyl chains. Peptide antimicrobial activity generally increased with increasing depth of peptide insertion. The overall results, in conjunction with molecular modeling, support an initial electrostatic interaction step in which bacterial membranes attract and bind peptide dimers onto the bacterial surface, followed by the "sinking" of the hydrophobic core segment to a peptide sequence-dependent depth of ϳ2.5-8 Å into the membrane, largely parallel to the membrane surface. Antimicrobial activity was likely enhanced by the fact that the peptide sequences contain AXXXA sequence motifs, which promote their dimerization, and possibly higher oligomerization, as assessed by SDS-polyacrylamide gel analysis and fluorescence resonance energy transfer experiments. The high selectivity of these peptides for nonmammalian membranes, combined with their activity toward a wide spectrum of Gram-negative and Gram-positive bacteria and yeast, while retaining water solubility, represent significant advantages of this class of peptides. Natural antimicrobial peptides are part of the innate immunity of a wide range of species ranging from insects and amphibians to mammals, including humans, defending against infections from bacteria, fungi, parasites, and enveloped viruses, with some peptides also effective against tumor cells (1, 2). Currently, data bases report over 800 * This work was supported in part by grants from the Canadian Infectious Diseases Society (to L. L. B.), the Canadian Institutes of Health Research (to C. M. D.), and the Natural Sciences and Engineering Research Council of Canada (to C. M. D.
Membrane-Active Peptides and Their Potential Biomedical Application
Pharmaceutics
Membrane-active peptides (MAPs) possess unique properties that make them valuable tools for studying membrane structure and function and promising candidates for therapeutic applications. This review paper provides an overview of the fundamental aspects of MAPs, focusing on their membrane interaction mechanisms and potential applications. MAPs exhibit various structural features, including amphipathic structures and specific amino acid residues, enabling selective interaction with multiple membranes. Their mechanisms of action involve disrupting lipid bilayers through different pathways, depending on peptide properties and membrane composition. The therapeutic potential of MAPs is significant. They have demonstrated antimicrobial activity against bacteria and fungi, making them promising alternatives to conventional antibiotics. MAPs can selectively target cancer cells and induce apoptosis, opening new avenues in cancer therapeutics. Additionally, MAPs serve as drug delivery vectors...
International Journal of Biological Macromolecules, 2022
Antimicrobial peptides (AMPs) attracted attention as potential source of novel antimicrobials. Multi-drug resistant (MDR) infections have emerged as a global threat to public health in recent years. Furthermore, due to rapid emergence of new diseases, there is pressing need for development of efficient antimicrobials. AMPs are essential part of the innate immunity in most living organisms, acting as the primary line of defense against foreign invasions. AMPs kill a wide range of microorganisms by primarily targeting cell membranes or intracellular components through a variety of ways. AMPs can be broadly categorized based on their physicochemical properties, structure, function, target and source of origin. The synthetic analogues produced either with suitable chemical modifications or with the use of suitable delivery systems are projected to eliminate the constraints of toxicity and poor stability commonly linked with natural AMPs. The concept of peptidomimetics is gaining ground around the world nowadays. Among the delivery systems, nanoparticles are emerging as potential delivery tools for AMPs, amplifying their utility against a variety of pathogens. In the present review, the broad classification of various AMPs, their mechanism of action (MOA), challenges associated with AMPs, current applications, and novel strategies to overcome the limitations have been discussed.
Membrane Active Peptides and Their Biophysical Characterization
In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide clues on the peptide–lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.
Frontiers in chemistry, 2018
Antimicrobial peptides (AMPs) are promising novel antibiotics since they have shown antimicrobial activity against a wide range of bacterial species, including multiresistant bacteria; however, toxicity is the major barrier to convert antimicrobial peptides into active drugs. A profound and proper understanding of the complex interactions between these peptides and biological membranes using biophysical tools and model membranes seems to be a key factor in the race to develop a suitable antimicrobial peptide therapy for clinical use. In the search for such therapy, different combined approaches with conventional antibiotics have been evaluated in recent years and demonstrated to improve the therapeutic potential of AMPs. Some of these approaches have revealed promising additive or synergistic activity between AMPs and chemical antibiotics. This review will give an insight into the possibilities that physicochemical tools can give in the AMPs research and also address the state of th...