Antimicrobial peptides and their use in medicine

The review presents the current classification of antimicrobial peptides (AMP), which are the main component of innate immunity. The mechanism of their action and the molecular basis of the formation of resistance towards these peptides are described. Data on the use of AMP for the treatment of various infectious diseases, as well as the state of the art in genetic therapy using AMP, are given.     

Defense peptides of plant immunity

Antimicrobial peptides (AMPs) are natural antibiotics produced by all living organisms to fight pathogens. They are important effector molecules of the immune system both in animals and plants. AMPs are diverse in structure and mode of action. Based on the homology of amino acid sequences and 3D structures several AMP families have been distinguished. They are defensins, thionins, lipid transfer proteins, hevein- and knottin-like peptides, and cyclotides. AMPs display broad-spectrum antimicrobial activity and thus show promise for the development of disease-resistant crops by genetic engineering and for the production of new-generation drugs. In this paper, the properties of the main AMP families (defensins and hevein-like peptides) and of new 4-Cys plant AMP family are reviewed.     

Defense peptides of plant immune system

Antimicrobial peptides (AMPs) are natural antibiotics produced by all living organisms to combat pathogens. They are important effector molecules of the immune system both in animals and plants. AMPs are diverse in structure and mode of action. Based on homology of amino acid sequences and 3D structures several AMP families have been distinguished. They are defensins, thionins, lipid transfer proteins, hevein- and knottin-like peptides, and cyclotides. AMPs display broad-spectrum antimicrobial activity and thus show promise for the development of disease- resistant crops by genetic engineering and for the production of new-generation drugs. In this paper, the properties of the main AMP families (defensins and hevein-like peptides) and of a new 4-Cys plant AMP family are reviewed.     

Antimicrobial properties and death-inducing mechanisms of saccharomycin,a biocide secreted by <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis>

We recently found that Saccharomyces cerevisiae (strain CCMI 885) secretes antimicrobial peptides (AMPs) derived from the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) that are active against various wine-related yeast and bacteria. Here, we show that several other S. cerevisiae strains also secrete natural biocide fractions during alcoholic fermentation, although at different levels, which correlates with the antagonistic effect exerted against non-Saccharomyces yeasts. We, therefore, term this biocide saccharomycin. The native AMPs were purified by gel-filtration chromatography and its antimicrobial activity was compared to that exhibited by chemically synthesized analogues (AMP1 and AMP2/3). Results show that the antimicrobial activity of the native AMPs is significantly higher than that of the synthetic analogues (AMP1 and AMP2/3), but a conjugated action of the two synthetic peptides is observed. Moreover, while the natural AMPs are active at pH 3.5, the synthetic peptides are not, since they are anionic and cannot dissolve at this acidic pH. These findings suggest that the molecular structure of the native biocide probably involves the formation of aggregates of several peptides that render them soluble under acidic conditions. The death mechanisms induced by the AMPs were also evaluated by means of epifluorescence microscopy-based methods. Sensitive yeast cells treated with the synthetic AMPs show cell membrane disruption, apoptotic molecular markers, and internalization of the AMPs. In conclusion, our work shows that saccharomycin is a natural biocide secreted by S. cerevisiae whose activity depends on the conjugated action of GAPDH-derived peptides. This study also reveals that S. cerevisiae secretes GAPDH-derived peptides as a strategy to combat other microbial species during alcoholic fermentations.     

Proteomics assisted profiling of antimicrobial peptide signatures from black pepper (<Emphasis Type="Italic">Piper nigrum</Emphasis> L.)

Plant antimicrobial peptides are the interesting source of studies in defense response as they are essential components of innate immunity which exert rapid defense response. In spite of abundant reports on the isolation of antimicrobial peptides (AMPs) from many sources, the profile of AMPs expressed/identified from single crop species under certain stress/physiological condition is still unknown. This work describes the AMP signature profile of black pepper and their expression upon Phytophthora infection using label-free quantitative proteomics strategy. The differential expression of 24 AMPs suggests that a combinatorial strategy is working in the defense network. The 24 AMP signatures belonged to the cationic, anionic, cysteine-rich and cysteine-free group. As the first report on the possible involvement of AMP signature in Phytophthora infection, our results offer a platform for further study on regulation, evolutionary importance and exploitation of theses AMPs as next generation molecules against pathogens.     

From "carpet" mechanism to de-novo designed diastereomeric cell-selective antimicrobial peptides

Living organisms of all types produce a large repertoire of gene-encoded, net positively charged, antimicrobial peptides as part of their innate immunity to microbial invasion. Despite significant variations in composition, length and secondary structure most antimicrobial peptides are active in micromolar concentrations, suggesting a common general mechanism for their mode of action. Many antimicrobial peptides bind bacterial phospholipid membranes up to a threshold concentration, followed by membrane permeation/disintegration (the "carpet" mechanism). Recent data suggest that the details of the permeation pathways may vary for different peptides and are assigned to different modes of action. Accumulating data reveal that the molecular basis for cell selectivity is the ability of peptides to specifically bind the negatively charged bacterial membrane, as well as their oligomeric state in solution and in the membrane. Based on the "carpet" mechanism and the role of the peptide oligomeric state, a novel group of diastereomeric (containing D- and L-amino acids) antimicrobial peptides were developed. These peptides may serve as promising templates for the future designs of antimicrobial peptides.     

Tool developments for structure-function studies of host defense peptides

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.     

蜜蜂抗菌肽研究及其应用进展

抗菌肽是一类由特定基因编码的小分子多肽,广泛分布于各种生物中,是生物天然免疫的重要效应分子,其对缺乏获得性免疫系统的昆虫尤为重要。蜜蜂是一种对环境极其重要的社会性模式昆虫,又有着极高的经济价值,因此蜜蜂抗菌肽有着较大的研究意义。本文对蜜蜂4种天然免疫抗菌肽(Apidaecin、Abaecin、Hymenoptaecin和Defensin)和蜂产品中的抗菌肽(Jelleines、Melittin和Apamin)研究进展进行了综述,介绍了它们的功能、作用机制及其应用,提出了蜜蜂抗菌肽未来可行的研究方向,旨在推动蜜蜂抗菌肽的研究。     

Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity

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.     

Novel alternatives to antibiotics: bacteriophages, bacterial cell wall hydrolases, and antimicrobial peptides

Extensive research has been conducted on the development of three groups of naturally occurring antimicrobials as novel alternatives to antibiotics: bacteriophages (phages), bacterial cell wall hydrolases (BCWH), and antimicrobial peptides (AMP). Phage therapies are highly efficient, highly specific, and relatively cost-effective. However, precautions have to be taken in the selection of phage candidates for therapeutic applications as some phages may encode toxins and others may, when integrated into host bacterial genome and converted to prophages in a lysogenic cycle, lead to bacterial immunity and altered virulence. BCWH are divided into three groups: lysozymes, autolysins, and virolysins. Among them, virolysins are the most promising candidates as they are highly specific and have the capability to rapidly lyse antibiotic-resistant bacteria on a generally species-specific basis. Finally, AMP are a family of natural proteins produced by eukaryotic and prokaryotic organisms or encoded by phages. AMP are of vast diversity in term of size, structure, mode of action, and specificity and have a high potential for clinical therapeutic applications.     

Mechanism of lipid bilayer perturbation by bactericidal membrane-active small molecules

Membrane-active small molecules (MASMs) are small organic molecules designed to reproduce the fundamental physicochemical properties of natural antimicrobial peptides: their cationic charge and amphiphilic character. This class of compounds has a promising broad range of antimicrobial activity and, at the same time, solves some major limitations of the peptides, such as their high production costs and low in vivo stability. Most cationic antimicrobial peptides act by accumulating on the surface of bacterial membranes and causing the formation of defects when a threshold is reached. Due to the drastically different structures of the two classes of molecules, it is not obvious that small-molecule antimicrobials act in the same way as natural peptides, and very few data are available on this aspect. Here we combined spectroscopic studies and molecular dynamics simulations to characterize the mechanism of action of two different MASMs. Our results show that, notwithstanding their simple structure, these molecules act just like antimicrobial peptides. They bind to the membrane surface, below the head-groups, and insert their apolar moieties in the core of the bilayer. Like many natural peptides, they cause the formation of defects when they reach a high coverage of the membrane surface. In addition, they cause membrane aggregation, and this property could contribute to their antimicrobial activity.     

Antimicrobial peptide resistance mechanisms of human bacterial pathogens

The critical role played by antimicrobial peptides (AMPs) in mammalian innate immunity is increasingly recognized. Bacteria differ in their intrinsic susceptibility to AMPs, and the relative resistance of some important human pathogens to these defense molecules is now appreciated as an important virulence phenotype. Experimental analysis has identified diverse mechanisms of bacterial AMP resistance including altered cell surface charge, active efflux, production of proteases or trapping proteins, and modification of host cellular processes. The contribution of these resistance mechanisms to pathogenesis is confirmed through direct comparison of wild-type bacteria and AMP-sensitive mutants using in vivo infection models. Knowledge of the molecular basis of bacterial AMP resistance may provide new targets for antimicrobial therapy of human infectious diseases.     

Defensins: antimicrobial peptides of innate immunity

The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.     

昆虫抗菌肽结构、性质和基因调控

昆虫抗菌肽是昆虫先天免疫系统中非常重要的一类效应分子。昆虫抗菌肽带正电荷,分子量小,大多数少于100个氨基酸残基。根据结构可以将昆虫抗菌肽分为一些不同的家族。昆虫抗菌肽不同的抗菌谱表明,它具有不同的作用机制。以果蝇为模式生物研究表明,昆虫抗菌肽的基因调控涉及到多个信号通路及大量的信号分子。     

The defensin–lipid interaction: Insights on the binding states of the human antimicrobial peptide HNP-1 to model bacterial membranes

Antimicrobial peptides are an important component of innate immunity and have generated considerable interest as a new potential class of natural antibiotics. The biological activity of antimicrobial peptides is strongly influenced by peptide–membrane interactions. Human Neutrophil Peptide 1 (HNP-1) is a 30 aminoacid peptide, belonging to the class of α-defensins. Many biophysical studies have been performed on this peptide to define its mechanism of action. Combining spectroscopic and thermodynamic analysis, insights on the interaction of the α-defensin with POPE:POPG:CL negative charged bilayers are given. The binding states of the peptide below and above the threshold concentration have been analyzed showing that the interaction with lipid bilayers is dependent by peptide concentration. These novel results that indicate how affinity and biological activities of natural antibiotics are depending by their concentration, might open new way of investigation of the antimicrobial mode of action.     

Piscidin,Fish Antimicrobial Peptide: Structure,Classification, Properties,Mechanism, Gene Regulation and Therapeutical Importance

Antimicrobial peptides (AMPs) are short molecules produced by almost all organisms. Fish AMPs contain innate immune components as their primary immune molecules. The fish AMPs include piscidins, hepcidins, defensins, cathelicidins and histone-derived peptides. Piscidin is potent and broad-spectrum; this peptide was conserved among Acanthopterygii superorder and is therapeutically important among other AMPs. It was present mainly in the tissues of gills, muscle, head-kidney, skin and intestine of teleost. Piscidin AMP family includes piscidin, moronecidin, pleurocidin, epinecidin, gaduscidin, misgurin, dicentracin, chrysophsin and myxinidin. This review reports the structural properties of various piscidin and their mode of action as it is important to know their mechanism how the peptide involved in antimicrobial activity. In addition, the gene expression of piscidin which influenced the immune responses, their pharmaceutical importance and biological applications were described. Overall, the review explains a broad spectrum of knowledge on piscidin, its classes and types, structure, cytotoxicity, membrane permeabilization, properties and therapeutical implications.

     

Antimicrobial peptides: key components of the innate immune system

Life-threatening infectious diseases are on their way to cause a worldwide crisis, as treating them effectively is becoming increasingly difficult due to the emergence of antibiotic resistant strains. Antimicrobial peptides (AMPs) form an ancient type of innate immunity found universally in all living organisms, providing a principal first-line of defense against the invading pathogens. The unique diverse function and architecture of AMPs has attracted considerable attention by scientists, both in terms of understanding the basic biology of the innate immune system, and as a tool in the design of molecular templates for new anti-infective drugs. AMPs are gene-encoded short (<100 amino acids), amphipathic molecules with hydrophobic and cationic amino acids arranged spatially, which exhibit broad spectrum antimicrobial activity. AMPs have been the subject of natural evolution, as have the microbes, for hundreds of millions of years. Despite this long history of co-evolution, AMPs have not lost their ability to kill or inhibit the microbes totally, nor have the microbes learnt to avoid the lethal punch of AMPs. AMPs therefore have potential to provide an important breakthrough and form the basis for a new class of antibiotics. In this review, we would like to give an overview of cationic antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which are highly expressed and found in humans, as well as a brief discussion about widely abundant, well characterized AMPs in mammals, in addition to pharmaceutical aspects and the additional functions of AMPs.     

Antimicrobial peptides: key components of the innate immune system

Life-threatening infectious diseases are on their way to cause a worldwide crisis, as treating them effectively is becoming increasingly difficult due to the emergence of antibiotic resistant strains. Antimicrobial peptides (AMPs) form an ancient type of innate immunity found universally in all living organisms, providing a principal first-line of defense against the invading pathogens. The unique diverse function and architecture of AMPs has attracted considerable attention by scientists, both in terms of understanding the basic biology of the innate immune system, and as a tool in the design of molecular templates for new anti-infective drugs. AMPs are gene-encoded short (<100 amino acids), amphipathic molecules with hydrophobic and cationic amino acids arranged spatially, which exhibit broad spectrum antimicrobial activity. AMPs have been the subject of natural evolution, as have the microbes, for hundreds of millions of years. Despite this long history of co-evolution, AMPs have not lost their ability to kill or inhibit the microbes totally, nor have the microbes learnt to avoid the lethal punch of AMPs. AMPs therefore have potential to provide an important breakthrough and form the basis for a new class of antibiotics. In this review, we would like to give an overview of cationic antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which are highly expressed and found in humans, as well as a brief discussion about widely abundant, well characterized AMPs in mammals, in addition to pharmaceutical aspects and the additional functions of AMPs.     

Function and therapeutic potential of host defence peptides.

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.