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1.
Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions 总被引:1,自引:0,他引:1
Cationic antimicrobial peptides (CAPs) occur as important innate immunity agents in many organisms, including humans, and offer a viable alternative to conventional antibiotics, as they physically disrupt the bacterial membranes, leading to membrane lysis and eventually cell death. In this work, we studied the biophysical and microbiological characteristics of designed CAPs varying in hydrophobicity levels and charge distributions by a variety of biophysical and biochemical approaches, including in-tandem atomic force microscopy, attenuated total reflection-FTIR, CD spectroscopy, and SDS-PAGE. Peptide structural properties were correlated with their membrane-disruptive abilities and antimicrobial activities. In bacterial lipid model membranes, a time-dependent increase in aggregated β-strand-type structure in CAPs with relatively high hydrophobicity (such as KKKKKKALFALWLAFLA-NH(2)) was essentially absent in CAPs with lower hydrophobicity (such as KKKKKKAAFAAWAAFAA-NH(2)). Redistribution of positive charges by placing three Lys residues at both termini while maintaining identical sequences minimized self-aggregation above the dimer level. Peptides containing four Leu residues were destructive to mammalian model membranes, whereas those with corresponding Ala residues were not. This finding was mirrored in hemolysis studies in human erythrocytes, where Ala-only peptides displayed virtually no hemolysis up to 320 μM, but the four-Leu peptides induced 40-80% hemolysis at the same concentration range. All peptides studied displayed strong antimicrobial activity against Pseudomonas aeruginosa (minimum inhibitory concentrations of 4-32 μM). The overall findings suggest optimum routes to balancing peptide hydrophobicity and charge distribution that allow efficient penetration and disruption of the bacterial membranes without damage to mammalian (host) membranes. 相似文献
2.
Bacterial exopolysaccharides provide protection against phagocytosis, opsonization, and dehydration and act as a major structural component of the extracellular matrix in biofilms. They contribute to biofilm-related resistance by acting as a diffusion barrier to positively charged antimicrobial agents including cationic antimicrobial peptides (CAPs). We previously created novel CAPs consisting of a nonamphipathic hydrophobic core flanked by Lys residues and containing a Trp residue in the hydrophobic segment as a fluorescent probe. Peptides of this type above a specific hydrophobicity threshold insert spontaneously into membranes and have antimicrobial activity against Gram-positive and Gram-negative bacteria at micromolar concentrations. Here we show that alginate, a polymer of beta-d-mannuronate and alpha-l-guluronate secreted by the cystic fibrosis pathogen Pseudomonas aeruginosa, induces an alpha-helical conformation detected by circular dichroism spectroscopy and blue shifts in Trp fluorescence maxima in peptides above the hydrophobicity threshold, changes typically observed upon association of such peptides with nonpolar (membrane) environments. Parallel effects were observed in the archetypical CAPs magainin II amide and cecropin P1. Fluorescence resonance energy transfer studies indicated that alginate induces peptide-peptide association only in peptides above the hydrophobicity threshold, suggesting that the hydrophilic alginate polymer behaves as an "auxiliary membrane" for the bacteria, demonstrating a unique protective role for biofilm matrices against CAPs. 相似文献
3.
Gone gene fishing: how to catch novel marine antimicrobials 总被引:11,自引:0,他引:11
Medical or health-promoting products of marine origin are often regarded with skepticism--some, such as shark fins and cod liver oil, are frequently perceived as low-tech "alternative treatments" largely because they have not been exploited to their full potential. The marine environment is an enormous source of biodiversity--80% of all life is found under the oceans' surfaces--yet very little of this rich resource has been utilized. Furthermore, most marine organisms rely heavily on antimicrobial components of their innate immune defenses to combat pathogens. The past three years has seen a revolution in the methods used to identify novel antimicrobials from marine sources; among the most promising are marine cationic antimicrobial peptides (CAPs). 相似文献
4.
Function and therapeutic potential of host defence peptides. 总被引:9,自引:0,他引:9
Cationic host defence (antimicrobial) peptides are an important component of the innate immune systems of a wide variety of plants, animals, and bacteria. Although most of these compounds have direct antimicrobial activities under specific conditions, a greater appreciation for the diversity of functions of these molecules is beginning to develop in the field. In addition to their directly antimicrobial activities, they also have a broad spectrum of activity on the host immune system, with both pro-inflammatory and anti-inflammatory effects being invoked. Increasingly sophisticated approaches to understand the role of host defence peptides in modulating innate immunity are already serving to guide the development of novel therapeutics. 相似文献
5.
Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity 总被引:20,自引:0,他引:20
Antimicrobial peptides are important host-defense molecules of innate immunity. Cathelicidins are a diverse family of potent, rapidly acting and broadly effective antimicrobial peptides, which are produced by a variety of cells. This review examines the classification, antimicrobial spectrum, mechanism of action, and regulation of cathelicidins. 相似文献
6.
Antimicrobial activities of heparin-binding peptides. 总被引:10,自引:0,他引:10
Emma Andersson Victoria Rydeng?rd Andreas Sonesson Matthias M?rgelin Lars Bj?rck Artur Schmidtchen 《European journal of biochemistry》2004,271(6):1219-1226
Antimicrobial peptides are effector molecules of the innate immune system. We recently showed that the human antimicrobial peptides alpha-defensin and LL-37 bind to glycosaminoglycans (heparin and dermatan sulphate). Here we demonstrate the obverse, i.e. structural motifs associated with heparin affinity (cationicity, amphipaticity, and consensus regions) may confer antimicrobial properties to a given peptide. Thus, heparin-binding peptides derived from laminin isoforms, von Willebrand factor, vitronectin, protein C inhibitor, and fibronectin, exerted antimicrobial activities against Gram-positive and Gram-negative bacteria. Similar results were obtained using heparin-binding peptides derived from complement factor C3 as well as consensus sequences for heparin-binding (Cardin and Weintraub motifs). These sequence motifs, and additional peptides, also killed the fungus Candida albicans. These data will have implications for the search for novel antimicrobial peptides and utilization of heparin-protein interactions should be helpful in the identification and purification of novel antimicrobial peptides from complex biological mixtures. Finally, consensus regions may serve as templates for de novo synthesis of novel antimicrobial molecules. 相似文献
7.
Arun Kumar Somavarapu Satish Balakrishnan Amit Kumar Singh Gautam David S Palmer Prasanna Venkatraman 《BMC structural biology》2014,14(1):1-14
Background
Many biologically active compounds bind to plasma transport proteins, and this binding can be either advantageous or disadvantageous from a drug design perspective. Human serum albumin (HSA) is one of the most important transport proteins in the cardiovascular system due to its great binding capacity and high physiological concentration. HSA has a preference for accommodating neutral lipophilic and acidic drug-like ligands, but is also surprisingly able to bind positively charged peptides. Understanding of how short cationic antimicrobial peptides interact with human serum albumin is of importance for developing such compounds into the clinics.Results
The binding of a selection of short synthetic cationic antimicrobial peptides (CAPs) to human albumin with binding affinities in the μM range is described. Competitive isothermal titration calorimetry (ITC) and NMR WaterLOGSY experiments mapped the binding site of the CAPs to the well-known drug site II within subdomain IIIA of HSA. Thermodynamic and structural analysis revealed that the binding is exclusively driven by interactions with the hydrophobic moieties of the peptides, and is independent of the cationic residues that are vital for antimicrobial activity. Both of the hydrophobic moieties comprising the peptides were detected to interact with drug site II by NMR saturation transfer difference (STD) group epitope mapping (GEM) and INPHARMA experiments. Molecular models of the complexes between the peptides and albumin were constructed using docking experiments, and support the binding hypothesis and confirm the overall binding affinities of the CAPs.Conclusions
The biophysical and structural characterizations of albumin-peptide complexes reported here provide detailed insight into how albumin can bind short cationic peptides. The hydrophobic elements of the peptides studied here are responsible for the main interaction with HSA. We suggest that albumin binding should be taken into careful consideration in antimicrobial peptide studies, as the systemic distribution can be significantly affected by HSA interactions. 相似文献8.
昆虫天然免疫反应分子机制研究进展 总被引:4,自引:0,他引:4
昆虫体内缺乏高等脊椎动物所具有的获得性免疫系统, 只能依赖发达的天然免疫系统抵抗细菌、 真菌、 病毒等外源病原物的侵染。本文概括了昆虫天然免疫反应发生和作用的分子机制相关进展, 重点阐述了重要免疫相关因子在昆虫天然免疫反应中的功能和作用机制。昆虫天然免疫反应分为体液免疫和细胞免疫两种, 二者共同作用完成对病原物的吞噬 (phagocytosis)、 集结 (nodulation)、 包囊 (encapsulation)、 凝结 (coagulation)和黑化(melanization)等。当昆虫受到外界病原物的侵染时, 首先通过体内的模式识别蛋白(pattern recognition proteins/receptor, PRPs)识别并结合病原物表面特有的模式分子(pathogen-associated molecular pattern, PAMPs), 继而一系列包括丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂在内的级联激活反应被激活和调控, 产生抗菌肽、 黑色素等免疫效应分子, 清除或杀灭外源物。抗菌肽是一类小分子量的阳离子肽, 具有广谱抗菌活性, 针对不同类型的病原物, 抗菌肽的产生机制也不尽相同。昆虫体内存在着两种信号转导途径调节抗菌肽的产生: 一是由真菌和大部分革兰氏阳性菌激活的Toll途径; 二是由革兰氏阴性菌激活的Imd途径(immune deficiency pathway)。这两个途径通过激活不同转录因子调控不同抗菌肽基因的表达参与昆虫体内的天然免疫反应。 相似文献
9.
10.
Human antimicrobial peptides: analysis and application 总被引:11,自引:0,他引:11
Antimicrobial peptides are innate host defense molecules that have a direct effect on bacteria, fungi and enveloped viruses. They are found in evolutionarily diverse species ranging from prokaryotes and plants to invertebrate and vertebrate animals. Humans express several families of antimicrobial peptides in myeloid cells and on various epithelial surfaces where they are poised to defend against pathogens. Recently, antimicrobial peptides from animals and plants have served as templates for the design of new therapeutic antibiotics. This review provides an introduction to the biology of human antimicrobial peptides, followed by a more detailed discussion of their isolation from tissues and biological fluids, their purification by gel electrophoresis and chromatography and assays of their antimicrobial activities. 相似文献
11.
Novel properties of antimicrobial peptides 总被引:7,自引:0,他引:7
Endogenous peptide antibiotics are known as evolutionarily old components of innate immunity. Due to interaction with cell membrane these peptides cause permeabilization of the membrane and lysis of invading microbes. However, some studies proved that antimicrobial peptides are universal multifunctional molecules and their functions extend far beyond simple antibiotics. In this review we present an overview of the general mechanism of action of antimicrobial peptides and discuss some of their additional properties, like antitumour activity, mitogenic activity, role in signal transduction pathways and adaptive immune response. 相似文献
12.
Ketil André Camilio Gerd Berge Chandra Sekhar Ravuri Øystein Rekdal Baldur Sveinbjørnsson 《Cancer immunology, immunotherapy : CII》2014,63(6):601-613
Malignant melanoma is the most aggressive and deadliest form of skin cancer due to its highly metastatic potential, which calls for new and improved therapies. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line of defense against pathogens, and several CAPs have shown promising potential as novel anticancer agents. Structure–activity relationship studies on the CAP bovine lactoferricin allowed us to de novo design short chemically modified lytic anticancer peptides. In the present study, we investigated the in vivo antitumor effects of LTX-315 against intradermally established B16 melanomas in syngeneic mice. Intratumoral administration of LTX-315 resulted in tumor necrosis and the infiltration of immune cells into the tumor parenchyma followed by complete regression of the tumor in the majority of the animals. LTX-315 induced the release of danger-associated molecular pattern molecules such as the high mobility group box-1 protein in vitro and the subsequent upregulation of proinflammatory cytokines such as interleukin (IL) 1β, IL6 and IL18 in vivo. Animals cured by LTX-315 treatment were protected against a re-challenge with live B16 tumor cells both intradermally and intravenously. Together, our data indicate that intratumoral treatment with LTX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent. 相似文献
13.
Peyrin-Biroulet L Vignal C Dessein R Simonet M Desreumaux P Chamaillard M 《Trends in microbiology》2006,14(10):432-438
Defensins and cathelicidins are prevalent and essential gastrointestinal cationic antimicrobial peptides (CAPs). However, these defensive peptides are not infallible because certain enteropathogens can overcome their protective function. Furthermore, impaired defensin synthesis has been linked to the occurrence of Crohn's disease (CD), a chronic inflammatory bowel disease. Recently, defective bacterial sensing through NOD1 and NOD2 has been related to reduced defensin production, CD predisposition and susceptibility to enteric infection. Hence, we propose that microbial sensors at the gut interface monitor the levels of these effector peptides, which might function as "danger" signals to confer tolerance and alert immunocytes. Further work is required to clarify how gastrointestinal CAPs are regulated and to assess their role in maintaining epithelial homeostasis and triggering adaptive immunity. 相似文献
14.
Cytotoxicity and cytotoxic molecules in invertebrates 总被引:17,自引:0,他引:17
Nappi AJ Ottaviani E 《BioEssays : news and reviews in molecular, cellular and developmental biology》2000,22(5):469-480
Although lacking the components that characterize the acquired immunity systems of vertebrates, invertebrates nevertheless possess effective general innate immune mechanisms which exhibit striking parallels with those of vertebrates. These innate immune systems include both cellular and humoral elements. Invertebrate phagocytes synthesize both oxygen-dependent and oxygen-independent molecules to combat infectious agents. Cytotoxic substances employed by invertebrates include reactive intermediates of oxygen and nitrogen, antimicrobial peptides, lectins, cytokine- and complement-like molecules, and quinoid intermediates of melanin. The signal transduction pathways that are involved in mediating the production of these substances appear to be very similar among animal species, suggesting a common ancestral origin for the innate immune systems. 相似文献
15.
Although they possess a well‐characterized ability to porate the bacterial membrane, emerging research suggests that cationic antimicrobial peptides (CAPs) can influence pathogen behaviour at levels that are sublethal. In this study, we investigated the interaction of polymyxin B and human neutrophil peptide (HNP‐1) with the human pathogen Streptococcus pyogenes. At sublethal concentrations, these CAPs preferentially targeted the ExPortal, a unique microdomain of the S. pyogenes membrane, specialized for protein secretion and processing. A consequence of this interaction was the disruption of ExPortal organization and a redistribution of ExPortal components into the peripheral membrane. Redistribution was associated with inhibition of secretion of certain toxins, including the SpeB cysteine protease and the streptolysin O (SLO) cytolysin, but not SIC, a protein that protects S. pyogenes from CAPs. These data suggest a novel function for CAPs in targeting the ExPortal and interfering with secretion of factors required for infection and survival. This mechanism may prove valuable for the design of new types of antimicrobial agents to combat the emergence of antibiotic‐resistant pathogens. 相似文献
16.
Recognition of antimicrobial peptides by a bacterial sensor kinase 总被引:24,自引:0,他引:24
Bader MW Sanowar S Daley ME Schneider AR Cho U Xu W Klevit RE Le Moual H Miller SI 《Cell》2005,122(3):461-472
17.
Peptidoglycan recognition protein (PGRP)-LE and PGRP-LC act synergistically in Drosophila immunity 总被引:2,自引:0,他引:2
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In innate immunity, pattern recognition molecules recognize cell wall components of microorganisms and activate subsequent immune responses, such as the induction of antimicrobial peptides and melanization in Drosophila. The diaminopimelic acid (DAP)-type peptidoglycan potently activates imd-dependent induction of antibacterial peptides. Peptidoglycan recognition protein (PGRP) family members act as pattern recognition molecules. PGRP-LC loss-of-function mutations affect the imd-dependent induction of antibacterial peptides and resistance to Gram-negative bacteria, whereas PGRP-LE binds to the DAP-type peptidoglycan, and a gain-of-function mutation induces constitutive activation of both the imd pathway and melanization. Here, we generated PGRP-LE null mutants and report that PGRP-LE functions synergistically with PGRP-LC in producing resistance to Escherichia coli and Bacillus megaterium infections, which have the DAP-type peptidoglycan. Consistent with this, PGRP-LE acts both upstream and in parallel with PGRP-LC in the imd pathway, and is required for infection-dependent activation of melanization in Drosophila. A role for PGRP-LE in the epithelial induction of antimicrobial peptides is also suggested. 相似文献
18.
Wang G 《Protein and peptide letters》2007,14(1):57-69
Antimicrobial peptides, or host defense peptides, are universal signaling and effector molecules in host defense and innate immunity. This article highlights various tools developed for cathelicidins and defensins, ranging from peptide identification, production, and structural biology, including the eight databases for antimicrobial peptides. Novel peptides can be identified from natural sources at both gene and protein levels. Solid-phase synthesis and bacterial expression are the two important methods for peptide production. Three-dimensional structures of antimicrobial peptides, primarily determined by solution NMR techniques, are essential for an in-depth understanding of the mode of action. The introduction of octanoyl phosphatidylglycerol as a bacterial membrane-mimetic model provides new insights into peptide-lipid interactions. The incorporation of structure and activity data into the antimicrobial peptide database (http://aps.unmc.edu/AP/main.html) will lead to an integrated understanding of these peptides via structural bioinformatics. 相似文献
19.
Evaluation of the inhibitory effects of human serum components on bactericidal activity of human beta defensin 3 总被引:3,自引:1,他引:2
Maisetta G Di Luca M Esin S Florio W Brancatisano FL Bottai D Campa M Batoni G 《Peptides》2008,29(1):1-6
Naturally occurring cationic antimicrobial peptides (CAPs) are an essential component of the innate immune system of multicellular organisms. At concentrations generally higher than those found in vivo, most CAPs exhibit strong antibacterial properties in vitro, but their activity may be inhibited by body fluids, a fact that could limit their future use as antimicrobial and/or immunomodulatory agents. In the present study, we evaluated the effects of human serum components on bactericidal activity of the human beta-defensin 3 (hBD-3), a CAP considered particularly promising for future therapeutic employment. Human serum diluted to 20% strongly inhibited the bactericidal activity of the peptide against both the Gram-positive species Staphylococcus aureus and the Gram-negative species Acinetobacter baumannii. Such activity was not restored in serum devoid of salts (dialyzed), pre-treated with protease inhibitors, or subjected to both of these treatments. The addition of physiological concentrations of NaCl, CaCl2, and human albumin in the bactericidal assay abolished bactericidal activity of hBD-3 against S. aureus, while it only partially inhibited the activity of the peptide against A. baumannii. Although a proteolytic activity of serum on hBD-3 was demonstrated at the protein level by Western blot, addition of physiological concentrations of trypsin to the bactericidal assay only partially affected the antibacterial properties of the peptide. Altogether, these results demonstrate a major role of mono-divalent cations and serum proteins on inhibition of hBD-3 antibacterial properties and indicate a relative lack in sensitivity of the bactericidal activity of this peptide to trypsin and trypsin-like proteases. 相似文献
20.
Robinson JA 《Current opinion in chemical biology》2011,15(3):379-386
There is growing interest in the design of synthetic molecules that mimic the structures and functions of epitopes found on the surface of peptides and proteins. Epitope mimetics can provide valuable tools to probe complex biological processes, as well as interesting leads for drug and vaccine discovery. One application of epitope mimetics is reviewed here, focusing on mimetics of the cationic antimicrobial peptides that form part of the innate immune response to microbial and viral infection in many organisms. Mimetics of these naturally occurring peptides and proteins may be useful to explore mechanisms of antimicrobial and immunomodulatory action, and as a potential source of new antibiotics to address one of the most pressing current threats to human health. 相似文献