Showing papers on "Antimicrobial peptides published in 2007"
TL;DR: The current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them are reviewed.
Abstract: To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them.
2,884 citations
TL;DR: It is demonstrated that a primary NF-κB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype.
Abstract: Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis-acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-kappaB, a master regulator of pro-inflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappaB through conditional ablation of NEMO (also called IkappaB kinase-gamma (IKKgamma)) or both IKK1 (IKKalpha) and IKK2 (IKKbeta)-IKK subunits essential for NF-kappaB activation-spontaneously caused severe chronic intestinal inflammation in mice. NF-kappaB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-kappaB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-kappaB signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.
1,025 citations
TL;DR: The striking parallels between the adult fly response and mammalian innate immune defences described below point to a common ancestry and validate the relevance of the fly defence as a paradigm for innate immunity.
Abstract: A hallmark of the potent, multifaceted antimicrobial defence of Drosophila melanogaster is the challenge-induced synthesis of several families of antimicrobial peptides by cells in the fat body. The basic mechanisms of recognition of various types of microbial infections by the adult fly are now understood, often in great detail. We have further gained valuable insight into the infection-induced gene reprogramming by nuclear factor-kappaB (NF-kappaB) family members under the dependence of complex intracellular signalling cascades. The striking parallels between the adult fly response and mammalian innate immune defences described below point to a common ancestry and validate the relevance of the fly defence as a paradigm for innate immunity.
799 citations
TL;DR: The role of cathelicidin in skin inflammatory responses is confirmed and an explanation for the pathogenesis of rosacea is suggested by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
Abstract: Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
707 citations
TL;DR: What is believed to be a previously unexpected role for vitamin D3 in innate immunity is demonstrated, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.
Abstract: An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.
636 citations
TL;DR: In this article, reactive oxygen (ROS) and reactive nitrogen (RNS) species have a dual function: they function as potent antimicrobial agents by virtue of their ability to kill microbial pathogens directly and participate as signaling molecules that regulate diverse physiological signaling pathways in neutrophils.
630 citations
TL;DR: This work reviews the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.
Abstract: Antibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization.
568 citations
TL;DR: The decreased antimicrobial activity at high peptide hydrophobicity can be explained by the strong peptide self-ass association which prevents the peptide from passing through the cell wall in prokaryotic cells, whereas increased peptideSelf-association had no effect on peptide access to eukaryotic membranes.
Abstract: In the present study, the 26-residue amphipathic α-helical antimicrobial peptide V13K L (Y. Chen et al., J. Biol. Chem. 2005, 280:12316-12329, 2005) was used as the framework to study the effects of peptide hydrophobicity on the mechanism of action of antimicrobial peptides. Hydrophobicity was systematically decreased or increased by replacing leucine residues with less hydrophobic alanine residues or replacing alanine residues with more hydrophobic leucine residues on the nonpolar face of the helix, respectively. Hydrophobicity of the nonpolar face of the amphipathic helix was demonstrated to correlate with peptide helicity (measured by circular dichroism spectroscopy) and self-associating ability (measured by reversed-phase high-performance liquid chromatography temperature profiling) in aqueous environments. Higher hydrophobicity was correlated with stronger hemolytic activity. In contrast, there was an optimum hydrophobicity window in which high antimicrobial activity could be obtained. Decreased or increased hydrophobicity beyond this window dramatically decreased antimicrobial activity. The decreased antimicrobial activity at high peptide hydrophobicity can be explained by the strong peptide self-association which prevents the peptide from passing through the cell wall in prokaryotic cells, whereas increased peptide self-association had no effect on peptide access to eukaryotic membranes.
552 citations
TL;DR: Evidence is provided that human antimicrobial peptides may be involved in skin immunity through stimulating cytokine/chemokine production, and participate in wound healing by promoting keratinocyte migration and proliferation.
485 citations
TL;DR: Interactions between human milk glycans, intestinal microflora, and intestinal mucosa surface glycans underlie ontogeny of innate mucosal immunity, pathobiology of enteric infection, and inflammatory bowel diseases.
Abstract: The neonatal adaptive immune system, relatively naive to foreign antigens, requires synergy with the innate immune system to protect the intestine. Goblet cells provide mucins, Paneth cells produce antimicrobial peptides, and dendritic cells (DCs) present luminal antigens. Intracellular signaling by Toll-like receptors (TLRs) elicits chemokines and cytokines that modulate inflammation. Enteric neurons and lymphocytes provide paracrine and endocrine signaling. However, full protection requires human milk. Breast-feeding reduces enteric infection and may reduce chronic disease in later life. Although human milk contains significant secretory immunoglobulin A (sIgA), most of its protective factors are constitutively expressed. Multifunctional milk components are nutrients whose partial digestion products inhibit pathogens. Cytokines, cytokine receptors, TLR agonists and antagonists, hormones, anti-inflammatory agents, and nucleotides in milk modulate inflammation. Human milk is rich in glycans (complex carbohydrates): As prebiotics, indigestible glycans stimulate colonization by probiotic organisms, modulating mucosal immunity and protecting against pathogens. Through structural homology to intestinal cell surface receptors, glycans inhibit pathogen binding, the essential first step of pathogenesis. Bioactive milk components comprise an innate immune system of human milk whereby the mother protects her nursing infant. Interactions between human milk glycans, intestinal microflora, and intestinal mucosa surface glycans underlie ontogeny of innate mucosal immunity, pathobiology of enteric infection, and inflammatory bowel diseases.
485 citations
TL;DR: In this paper, an updated review of how cationic antimicrobial peptides are able to affect bacterial killing, with a focus on internal targets, is presented, where some peptides clearly act differently and other intracellular target sites have been identified.
Abstract: Cationic antimicrobial peptides are a novel type of antibiotic offering much potential in the treatment of microbial-related diseases. They offer many advantages for commercial development, including a broad spectrum of action and modest size. However, despite the identification or synthetic production of thousands of such peptides, the mode of action remains elusive, except for a few examples. While the dogma for the mechanism of action of antimicrobial peptides against bacteria is believed to be through pore formation or membrane barrier disruption, some peptides clearly act differently and other intracellular target sites have been identified. This article presents an updated review of how cationic antimicrobial peptides are able to affect bacterial killing, with a focus on internal targets.
TL;DR: Future studies to further define mechanisms by which defensins and other host factors regulate the composition of the intestinal microbiota will likely provide new insights into intestinal homeostasis and new therapeutic strategies for inflammatory and infectious diseases of the bowel.
TL;DR: Permeability and antimicrobial function are both co-regulated and interdependent, overlapping through the dual activities of their lipid/protein constituents, and the key role of epithelial structure in antimicrobial defense is emphasized.
Abstract: Since life in a terrestrial environment threatens mammals continuously with desiccation, the structural, cellular, biochemical, and regulatory mechanisms that sustain permeability barrier homeostasis have justifiably comprised a major thrust of prior and recent research on epidermal barrier function. Yet, the epidermis mediates a broad set of protective ‘barrier’ functions that includes defense against pathogen challenges. Permeability and antimicrobial function are both co-regulated and interdependent, overlapping through the dual activities of their lipid/protein constituents. Most of the defensive (barrier) functions of the epidermis localize to the stratum corneum (SC), which limits pathogen colonization through its low water content, acidic pH, resident (normal) microflora, and surface-deposited antimicrobial lipids (1° free fatty acid). These various barrier functions are largely mediated by either the corneocyte or the extracellular matrix, and it is both the localization and the organization of secreted hydrophobic lipids into characteristic lamellar bilayers that is critical not only for permeability barrier function, but also for antimicrobial function through its contribution to the maintenance of SC integrity. Low constitutive levels of antimicrobial peptides under basal conditions emphasize the key role of epithelial structure in antimicrobial defense. But antimicrobial peptide synthesis and delivery to the SC interstices accelerates after external insults to the barrier.
TL;DR: The identified genes include classes of defensins, thionins, lipid transfer proteins, and snakins, plus other protease inhibitors, pollen allergens, and uncharacterized gene families, and it is estimated that these classes of genes account for approximately 2-3% of the gene repertoire of each model species.
Abstract: Multicellular organisms produce small cysteine-rich antimicrobial peptides as an innate defense against pathogens. While defensins, a well-known class of such peptides, are common among eukaryotes, there are other classes restricted to the plant kingdom. These include thionins, lipid transfer proteins and snakins. In earlier work, we identified several divergent classes of small putatively secreted cysteine-rich peptides (CRPs) in legumes [Graham et al. (2004)Plant Physiol. 135, 1179-97]. Here, we built sequence motif models for each of these classes of peptides, and iteratively searched for related sequences within the comprehensive UniProt protein dataset, the Institute for Genomic Research's 33 plant gene indices, and the entire genomes of the model dicot, Arabidopsis thaliana, and the model monocot and crop species, Oryza sativa (rice). Using this search strategy, we identified approximately 13,000 plant genes encoding peptides with common features: (i) an N-terminal signal peptide, (ii) a small divergent charged or polar mature peptide with conserved cysteines, (iii) a similar intron/exon structure, (iv) spatial clustering in the genomes studied, and (v) overrepresentation in expressed sequences from reproductive structures of specific taxa. The identified genes include classes of defensins, thionins, lipid transfer proteins, and snakins, plus other protease inhibitors, pollen allergens, and uncharacterized gene families. We estimate that these classes of genes account for approximately 2-3% of the gene repertoire of each model species. Although 24% of the genes identified were not annotated in the latest Arabidopsis genome releases (TIGR5, TAIR6), we confirmed expression via RT-PCR for 59% of the sequences attempted. These findings highlight limitations in current annotation procedures for small divergent peptide classes.
TL;DR: Differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, were determined and risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosis with pulmonary TB.
Abstract: Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacille Calmette Guerin and Mycobacterium tuberculosis was impaired 7.3- and 3.1-fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependent manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB.
TL;DR: Elucidation of the effect of 1,25(OH)(2)D(3) on cathelicidin expression in NHBE cells and CF bronchial epithelial cells will aid in the development of novel therapeutic agents for treatment of airway infections in CF.
TL;DR: Antimicrobial peptides are interesting compounds in plant health because there is a need for new products in plant protection that fit into the new regulations, and they are the basis for the design of new synthetic analogues.
Abstract: Several diseases caused by viruses, bacteria and fungi affect plant crops, resulting in losses and decreasing the quality and safety of agricultural products. Plant disease control relies mainly on chemical pesticides that are currently subject to strong restrictions and regulatory requirements. Antimicrobial peptides are interesting compounds in plant health because there is a need for new products in plant protection that fit into the new regulations. Living organisms secrete a wide range of antimicrobial peptides produced through ribosomal (defensins and small bacteriocins) or non-ribosomal synthesis (peptaibols, cyclopeptides and pseudopeptides). Several antimicrobial peptides are the basis for the design of new synthetic analogues, have been expressed in transgenic plants to confer disease protection or are secreted by microorganisms that are active ingredients of commercial biopesticides.
TL;DR: Differences in susceptibility to chytridiomycosis among four Australian species after experimental infection with B. dendrobatidis are demonstrated, and it is observed that circulating granulocyte, but not lymphocyte, counts differed between infected and uninfected Lit.
Abstract: Innate immune mechanisms of defense are especially important to ectothermic vertebrates in which adaptive immune responses may be slow to develop. One innate defense in amphibian skin is the release of abundant quantities of antimicrobial peptides. Chytridiomycosis is an emerging infectious disease of amphibians caused by the skin fungus, Batrachochytrium dendrobatidis. Susceptibility to chytridiomycosis varies among species, and mechanisms of disease resistance are not well understood. Previously, we have shown that Australian and Panamanian amphibian species that possess skin peptides that effectively inhibit the growth of B. dendrobatidis in vitro tend to survive better in the wild or are predicted to survive the first encounter with this lethal pathogen. For most species, it has been difficult to experimentally infect individuals with B. dendrobatidis and directly evaluate both survival and antimicrobial peptide defenses. Here, we demonstrate differences in susceptibility to chytridiomycosis among four Australian species (Litoria caerulea, Litoria chloris, Mixophyes fasciolatus and Limnodynastes tasmaniensis) after experimental infection with B. dendrobatidis, and show that the survival rate increases with the in vitro effectiveness of the skin peptides. We also observed that circulating granulocyte, but not lymphocyte, counts differed between infected and uninfected Lit. chloris. This suggests that innate granulocyte defenses may be activated by pathogen exposure. Taken together, our data suggest that multiple innate defense mechanisms are involved in resistance to chytridiomycosis, and the efficacy of these defenses varies by amphibian species.
TL;DR: 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.
Abstract: 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.
TL;DR: It is shown that AMPs induce resistance mechanisms in CA‐MRSA via the aps AMP sensor/regulator system, including the d‐alanylation of teichoic acids and putative AMP transport systems such as the vraFG transporter, for which it is demonstrated a function in AMP resistance.
Abstract: Summary
Staphylococcus aureus is a leading cause of hospital-associated and, more recently, community-associated infections caused by highly virulent methicillin-resistant strains (CA-MRSA). S. aureus survival in the human host is largely defined by the ability to evade attacks by antimicrobial peptides (AMPs) and other mechanisms of innate host defence. Here we show that AMPs induce resistance mechanisms in CA-MRSA via the aps AMP sensor/regulator system, including (i) the d-alanylation of teichoic acids, (ii) the incorporation of lysyl-phosphatidylglycerol in the bacterial membrane and a concomitant increase in lysine biosynthesis, and (iii) putative AMP transport systems such as the vraFG transporter, for which we demonstrate a function in AMP resistance. In contrast to the aps system of S. epidermidis, induction of the aps response in S. aureus was AMP-selective due to structural differences in the AMP binding loop of the ApsS sensor protein. Finally, using a murine infection model, we demonstrate the importance of the aps regulatory system in S. aureus infection. This study shows that while significant interspecies differences exist in the AMP–aps interaction, the AMP sensor system aps is functional and efficient in promoting resistance to a variety of AMPs in a clinically relevant strain of the important human pathogen S. aureus.
TL;DR: This study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development.
Abstract: To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human β-defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Furthermore, our data indicate that a very short, extracellular loop with a high density of negative charges in the sensor protein is responsible for antimicrobial peptide binding and the observed specificity for cationic antimicrobial peptides. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development.
TL;DR: There is preference for certain residues at N and C termini, which helps to demarcate them from non-antibacterial peptides, which the authors hope will prove to be a boon to combat the dreadful antibiotic resistant bacteria.
Abstract: Antibacterial peptides are important components of the innate immune system, used by the host to protect itself from different types of pathogenic bacteria. Over the last few decades, the search for new drugs and drug targets has prompted an interest in these antibacterial peptides. We analyzed 486 antibacterial peptides, obtained from antimicrobial peptide database APD, in order to understand the preference of amino acid residues at specific positions in these peptides. It was observed that certain types of residues are preferred over others in antibacterial peptides, particularly at the N and C terminus. These observations encouraged us to develop a method for predicting antibacterial peptides in proteins from their amino acid sequence. First, the N-terminal residues were used for predicting antibacterial peptides using Artificial Neural Network (ANN), Quantitative Matrices (QM) and Support Vector Machine (SVM), which resulted in an accuracy of 83.63%, 84.78% and 87.85%, respectively. Then, the C-terminal residues were used for developing prediction methods, which resulted in an accuracy of 77.34%, 82.03% and 85.16% using ANN, QM and SVM, respectively. Finally, ANN, QM and SVM models were developed using N and C terminal residues, which achieved an accuracy of 88.17%, 90.37% and 92.11%, respectively. All the models developed in this study were evaluated using five-fold cross validation technique. These models were also tested on an independent or blind dataset. Among antibacterial peptides, there is preference for certain residues at N and C termini, which helps to demarcate them from non-antibacterial peptides. Both the termini play a crucial role in imparting the antibacterial property to these peptides. Among the methods developed, SVM shows the best performance in predicting antibacterial peptides followed by QM and ANN, in that order. AntiBP (Antibacterial peptides) will help in discovering efficacious antibacterial peptides, which we hope will prove to be a boon to combat the dreadful antibiotic resistant bacteria. A user friendly web server has also been developed to help the biological community, which is accessible at http://www.imtech.res.in/raghava/antibp/
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TL;DR: It is suggested that symbiotic bacteria with the ability to persist in the presence of mucosal peptides may inhibit infection and colonization of the skin by Bd and increase the effectiveness of innate defense mechanisms in the skin.
TL;DR: In this paper, the authors describe peptidomimetic oligomers that show rapid, nonhemolytic, broad-spectrum bactericidal properties in mice and do not induce the emergence of resistance.
Abstract: We describe peptidomimetic oligomers that show rapid, nonhemolytic, broad-spectrum bactericidal properties in mice and do not induce the emergence of resistance. The oligomers contain acyl chains, which prevent the formation of stable secondary structure. This design appears advantageous over conventional antimicrobial peptides with respect to in vivo efficacy and safety, and may provide a convenient platform for the development of peptide antibiotics.
TL;DR: This work proposes a model of activation by antimicrobial peptides via disruption of the cation bridges and/or by acidification of the periplasm through destabilization of the interaction network.
TL;DR: Recent literature is highlighted, showing that antimicrobial peptides are associated with several human conditions including infectious and inflammatory diseases, and to discuss current clinical development of peptide-based therapeutics for future use.
Abstract: Antimicrobial peptides have emerged as promising agents against antibiotic-resistant pathogens. They represent essential components of the innate immunity and permit humans to resist infection by microbes. These gene-encoded peptides are found mainly in phagocytes and epithelial cells, showing a direct activity against a wide range of microorganisms. Their role has now broadened from that of simply endogenous antibiotics to multifunctional mediators, and their antimicrobial activity is probably not the only primary function. Although antimicrobial peptide deficiency, dysregulation, or overproduction is not known to be a direct cause of any single human disease, numerous studies have now provided compelling evidence for their involvement in the complex network of immune responses and inflammatory diseases, thereby influencing diverse processes including cytokine release, chemotaxis, angiogenesis, wound repair, and adaptive immune induction. The purpose of this review is to highlight recent literature, showing that antimicrobial peptides are associated with several human conditions including infectious and inflammatory diseases, and to discuss current clinical development of peptide-based therapeutics for future use.
TL;DR: This work has extended the repertoire of activities for AMPs to include immunostimulatory and immunomodulatory capacity as a catalyst for secondary host defense mechanisms and will lead to novel alternative approaches to the treatment of human pathogenic disorders.
Abstract: Antimicrobial peptides (AMPs) are an evolutionarily conserved component of the innate immune system that defend against invading bacteria, viruses, and fungi through membrane or metabolic disruption. The efficiency of host defense via AMPs derives from the ability of these peptides to quickly identify and eradicate foreign pathogens through precise biochemical mechanisms. Recent advances in this field have expanded the repertoire of activities for AMPs to include immunostimulatory and immunomodulatory capacity as a catalyst for secondary host defense mechanisms. Further scrutiny of the biochemical and regulatory mechanisms of AMPs will lead to novel alternative approaches to the treatment of human pathogenic disorders.
TL;DR: It is demonstrated here that fluorinated derivatives of two host defense antimicrobial peptides, buforin and magainin, display moderately better protease stability while retaining, or exhibiting significantly increased bacteriostatic activity.
Abstract: Selective fluorination of peptides results in increased chemical and thermal stability with simultaneously enhanced hydrophobicity. We demonstrate here that fluorinated derivatives of two host defense antimicrobial peptides, buforin and magainin, display moderately better protease stability while retaining, or exhibiting significantly increased bacteriostatic activity. Four fluorinated analogues in the buforin and two in the magainin series were prepared and analyzed for (1) their ability to resist hydrolytic cleavage by trypsin; (2) their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains; and (3) their hemolytic activity. All but one fluorinated peptide (M2F5) showed retention, or significant enhancement, of antimicrobial activity. The peptides also showed modest increases in protease resistance, relative to the parent peptides. Only one of the six fluorinated peptides (BII1F2) was degraded by trypsin at a slightly faster rate than the parent peptide. Hemolytic activit...
TL;DR: This work reviews how SA and GAS avoid the bactericidal activities of cationic antimicrobial peptides, delay phagocytes recruitment, escape neutrophil extracellular traps, inhibit complement and antibody opsonization functions, impair phagocytotic uptake, resist oxidative burst killing, and promote phagocyte lysis or apoptosis.
Abstract: Staphylococcus aureus (SA) and group A Streptococcus (GAS) are prominent Gram-positive bacterial pathogens, each associated with a variety of mucosal and invasive human infections. SA and GAS systemic disease reflects diverse abilities of these pathogens to resist clearance by the multifaceted defenses of the human innate immune system. Here we review how SA and GAS avoid the bactericidal activities of cationic antimicrobial peptides, delay phagocyte recruitment, escape neutrophil extracellular traps, inhibit complement and antibody opsonization functions, impair phagocytotic uptake, resist oxidative burst killing, and promote phagocyte lysis or apoptosis. Understanding the molecular basis of SA and GAS innate immune resistance reveals novel therapeutic targets for treatment or prevention of invasive human infections. These future therapies envision alternatives to direct microbial killing, such as blocking disease progression by neutralizing specific virulence factors or boosting key innate immune defenses.
TL;DR: The general opinion that 20–30 different antimicrobial peptides can protect an animal can be doubted and the strong capability of innate immunity and molecular genetics of amphibian ecological diversification is considered.