Showing papers on "Antimicrobial peptides published in 2015"
TL;DR: The ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues, which bode well for developing plant AMP as potential therapeutics and for protection of crops through transgenic methods.
Abstract: Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.
386 citations
TL;DR: These findings establish a mechanism that determines the stability of prominent members of a healthy microbiota during perturbation and have identified a mechanism for lipopolysaccharide (LPS) modification in the phylum Bacteroidetes that increases AMP resistance by four orders of magnitude.
Abstract: Resilience to host inflammation and other perturbations is a fundamental property of gut microbial communities, yet the underlying mechanisms are not well understood. We have found that human gut microbes from all dominant phyla are resistant to high levels of inflammation-associated antimicrobial peptides (AMPs) and have identified a mechanism for lipopolysaccharide (LPS) modification in the phylum Bacteroidetes that increases AMP resistance by four orders of magnitude. Bacteroides thetaiotaomicron mutants that fail to remove a single phosphate group from their LPS were displaced from the microbiota during inflammation triggered by pathogen infection. These findings establish a mechanism that determines the stability of prominent members of a healthy microbiota during perturbation.
306 citations
TL;DR: These studies which describe multi-step mechanisms which are adopted by various AMPs in nature and may advance the approach to the development of a new generation of effective antimicrobial therapeutics are reviewed.
Abstract: Antimicrobial peptides (AMPs) are showing increasing promise as potential candidate antibacterial drugs in the face of the rapidly emerging bacterial resistance to conventional antibiotics in recent years. The target of these peptides is the microbial membrane and there are numerous models to explain their mechanism of action ranging from pore formation to general membrane disruption. The interaction between the AMP and the target membrane is critical to the specificity and activity of these peptides. However, a precise understanding of the relationship between antimicrobial peptide structure and their cytolytic function in a range of organisms is still lacking. This is a result of the complex nature of the interactions of AMPs with the cell membrane, the mechanism of which can vary considerably between different classes of antimicrobia peptides. A wide range of biophysical techniques have been used to study the influence of a number of peptide and membrane properties on the cytolytic activity of these peptides in model membrane systems. Central to characterisation of this interaction is a quantitative analysis of the binding of peptide to the membrane and the coherent dynamic changes in membrane structure. Recently, dual polarization interferometry has been used to perform an in depth analysis of antimicrobial peptide induced membrane perturbation and with new mass-structure co-fitting kinetic analysis have allowed a real-time label free analysis of binding affinity and kinetics. We review these studies which describe multi-step mechanisms which are adopted by various AMPs in nature and may advance our approach to the development of a new generation of effective antimicrobial therapeutics.
291 citations
TL;DR: This work focuses on Bacillus-derived AMPs as a novel alternative approach to antibacterial drug development and provides an overview of the biosynthesis, mechanisms of action, applications, and effectiveness of different AMPs produced by members of the Bacillus genus.
Abstract: The rapid onset of resistance reduces the efficacy of most conventional antimicrobial drugs and is a general cause of concern for human well-being. Thus, there is great demand for a continuous supply of novel antibiotics to combat this problem. Bacteria-derived antimicrobial peptides (AMPs) have long been used as food preservatives; moreover, prior to the development of conventional antibiotics, these AMPs served as an efficient source of antibiotics. Recently, peptides produced by members of the genus Bacillus were shown to have a broad spectrum of antimicrobial activity against pathogenic microbes. Bacillus-derived AMPs can be synthesized both ribosomally and nonribosomally and can be classified according to peptide biosynthesis, structure, and molecular weight. The precise mechanism of action of these AMPs is not yet clear; however, one proposed mechanism is that these AMPs kill bacteria by forming channels in and (or) disrupting the bacterial cell wall. Bacillus-derived AMPs have potential in the pharmaceutical industry, as well as the food and agricultural sectors. Here, we focus on Bacillus-derived AMPs as a novel alternative approach to antibacterial drug development. We also provide an overview of the biosynthesis, mechanisms of action, applications, and effectiveness of different AMPs produced by members of the Bacillus genus, including several recently identified novel AMPs.
267 citations
TL;DR: Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens.
256 citations
TL;DR: A novel, unifying peptide classification system is proposed to emphasize the enormous diversity in peptide synthesis and consequent complexity of the still expanding knowledge on the plant peptidome.
Abstract: Peptides fulfill a plethora of functions in plant growth, development, and stress responses. They act as key components of cell-to-cell communication, interfere with signaling and response pathways, or display antimicrobial activity. Strikingly, both the diversity and amount of plant peptides have been largely underestimated. Most characterized plant peptides to date acting as small signaling peptides or antimicrobial peptides are derived from nonfunctional precursor proteins. However, evidence is emerging on peptides derived from a functional protein, directly translated from small open reading frames (without the involvement of a precursor) or even encoded by primary transcripts of microRNAs. These novel types of peptides further add to the complexity of the plant peptidome, even though their number is still limited and functional characterization as well as translational evidence are often controversial. Here, we provide a comprehensive overview of the reported types of plant peptides, including their described functional and structural properties. We propose a novel, unifying peptide classification system to emphasize the enormous diversity in peptide synthesis and consequent complexity of the still expanding knowledge on the plant peptidome.
238 citations
TL;DR: A clear and surprisingly specific role for IL-17 in protection against the fungus Candida albicans is revealed, and the implications for clinical therapies for both autoimmune conditions and fungal infections are considered.
Abstract: IL-17 (IL-17A) has emerged as a key mediator of protection against extracellular microbes, but this cytokine also drives pathology in various autoimmune diseases. Overwhelming data in both humans and mice reveal a clear and surprisingly specific role for IL-17 in protection against the fungus Candida albicans, a commensal microbe of the human oral cavity, gastrointestinal tract, and reproductive mucosa. The IL-17 pathway regulates antifungal immunity through upregulation of proinflammatory cytokines, including IL-6, neutrophil-recruiting chemokines (e.g., CXCL1 and CXCL5), and antimicrobial peptides (e.g., defensins), which act in concert to limit fungal overgrowth. This review focuses on diseases caused by C. albicans, the role of IL-17-mediated immunity in candidiasis, and the implications for clinical therapies for both autoimmune conditions and fungal infections.
224 citations
TL;DR: Peptides package was designed for allowing the quick and easy computation of ten structural characteristics own of the antimicrobial peptides, with the aim of generating data for increase the accuracy in classification and design of new amino acid sequences.
Abstract: Antimicrobial peptides (AMP) are a promising source of antibiotics with a broad spectrum activity against bacteria and low incidence of developing resistance. The mechanism by which an AMP executes its function depends on a set of computable physicochemical properties from the amino acid sequence. Peptides package was designed for allowing the quick and easy computation of ten structural characteristics own of the antimicrobial peptides, with the aim of generating data for increase the accuracy in classification and design of new amino acid sequences. Moreover, the options to read and plot XVG output files from GROMACS molecular dynamics package was included.
220 citations
TL;DR: It is found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development.
217 citations
TL;DR: The platelet–bacteria interplay is a complex game; its fine analysis is complicated by the fact that the inflammatory component adds to the aggregation response.
Abstract: Platelets can be considered sentinels of vascular system due to their high number in the circulation and to the range of functional immunoreceptors they express. Platelets express a wide range of potential bacterial receptors, including complement receptors, FcγRII, Toll-Like Receptors but also integrins conventionally described in the hemostatic response, such as GPIIb-IIIa or GPIb. Bacteria bind these receptors either directly, or indirectly via fibrinogen, fibronectin, the first complement C1q, the von Willebrand Factor, etc. The fate of platelet bound bacteria is questioned. Several studies reported the ability of activated platelets to internalize bacteria such as Staphylococcus aureus or Porphyromonas gingivalis, though there is no clue on what happens thereafter. Are they sheltered from the immune system in the cytoplasm of platelets or are they lysed? Indeed, while the presence of phagolysosome has not been demonstrated in platelets, they contain antimicrobial peptides that were shown to be efficient on S. aureus. Besides, the fact that bacteria can bind to platelets via receptors involved in hemostasis suggests that they may induce aggregation; this has indeed been described for Streptococcus sanguinis, S. epidermidis or C. pneumoniae. On the other hand, platelets are able to display an inflammatory response to an infectious triggering. We, and others, have shown that platelet release soluble immunomodulatory factors upon stimulation by bacterial components. Moreover, interactions between bacteria and platelets are not limited to only these two partners. Indeed, platelets are also essential for the formation of Neutrophil Extracellular Traps by neutrophils, resulting in bacterial clearance by trapping bacteria and concentrating antibacterial factors but in enhancing thrombosis. In conclusion, the platelet-bacteria interplay is a complex game; its fine analysis is complicated by the fact that the inflammatory component adds to the aggregation response.
192 citations
TL;DR: The design of various types of macromolecular architectures with control of structural parameters such as hydrophobicity/hydrophilicity balance, molecular weight, and ionic groups will be emphasized in order to achieve strong antimicrobial activities while minimizing toxicity to mammalian cells.
TL;DR: The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies, and the contributions of individual amino acids with respect to the peptides antibacterial properties.
Abstract: The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochemical properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics.
TL;DR: The 2014 results support that combination therapy is preferred over monotherapy in treating biofilms and 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides.
Abstract: This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.
TL;DR: A potential novel role of the intestinal epithelium and microbiome in the progression of ALS is suggested and principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild‐type mice.
Abstract: Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.
TL;DR: Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.
Abstract: Amyloid plaques, the hallmark of Alzheimer’s disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.
TL;DR: This work reviews the available strategies for their synthesis, bioinformatics tools for the rational design of antimicrobial peptides with enhanced therapeutic indices, hurdles and shortcomings limiting the large-scale production of AMPs, as well as the challenges that the pharmaceutical industry faces on their use as therapeutic agents.
Abstract: Antimicrobial peptides are small molecules with activity against bacteria, yeasts, fungi, viruses, bacteria, and even tumor cells that make these molecules attractive as therapeutic agents. Due to the alarming increase of antimicrobial resistance, interest in alternative antimicrobial agents has led to the exploitation of antimicrobial peptides, both synthetic and from natural sources. Thus, many peptide-based drugs are currently commercially available for the treatment of numerous ailments, such as hepatitis C, myeloma, skin infections, and diabetes. Initial barriers are being increasingly overcome with the development of cost-effective, more stable peptides. Herein, we review the available strategies for their synthesis, bioinformatics tools for the rational design of antimicrobial peptides with enhanced therapeutic indices, hurdles and shortcomings limiting the large-scale production of AMPs, as well as the challenges that the pharmaceutical industry faces on their use as therapeutic agents.
TL;DR: This minireview summarizes recent findings on alternative, non-lytic modes of antimicrobial action with an emphasis to the experimental approaches used to clarify each step of their intracellular action, i.e. the cell penetration mechanism, intrACEllular localization and molecular mechanisms of antibacterial action.
Abstract: Antimicrobial peptides (AMPs) are a large class of innate immunity effectors with a remarkable capacity to inactivate microorganisms. Their ability to kill bacteria by membranolytic effects has been well established. However, a lot of evidence points to alternative, non-lytic modes of action for a number of AMPs, which operate through interactions with specific molecular targets. It has been reported that non-membrane-permeabilizing AMPs can bind to and inhibit DNA, RNA or protein synthesis processes, inactivate essential intracellular enzymes, or affect membrane septum formation and cell wall synthesis. This minireview summarizes recent findings on these alternative, non-lytic modes of antimicrobial action with an emphasis to the experimental approaches used to clarify each step of their intracellular action, i.e. the cell penetration mechanism, intracellular localization and molecular mechanisms of antibacterial action. Despite the fact that such data exists for a large number of peptides, our analysis indicates that only for a small number of AMPs sufficient data have been collected to support a mode of action with an authentic and substantial contribution by intracellular targeting. In most cases, peptides with non-lytic features have not been thoroughly analyzed, or only a single aspect of their mode of action has been taken into consideration and therefore their mechanism of action can only be hypothesized. A more detailed knowledge of this class of AMPs would be important in the design of novel antibacterial agents against unexploited targets, endowed with the capacity to penetrate into pathogen cells and kill them from within.
TL;DR: The design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity is reported, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude.
Abstract: α-Helical antimicrobial peptides (AMPs) generally have facially amphiphilic structures that may lead to undesired peptide interactions with blood proteins and self-aggregation due to exposed hydrophobic surfaces. Here we report the design of a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. The radially amphiphilic structure enables the polypeptide to bind effectively to the negatively charged bacterial surface and exhibit high antimicrobial activity against both gram-positive and gram-negative bacteria. Moreover, the shielding of the hydrophobic core by the charged exterior shell decreases nonspecific interactions with eukaryotic cells, as evidenced by low hemolytic activity, and protects the polypeptide backbone from proteolytic degradation. The radially amphiphilic polypeptides can also be used as effective adjuvants, allowing improved permeation of commercial antibiotics in bacteria and enhanced antimicrobial activity by one to two orders of magnitude. Designing AMPs bearing this unprecedented, unique radially amphiphilic structure represents an alternative direction of AMP development; radially amphiphilic polypeptides may become a general platform for developing AMPs to treat drug-resistant bacteria.
TL;DR: The hypothesis that the encapsulation of the frog-skin derived AMP temporin B (TB) into chitosan nanoparticles (CS-NPs) could increase peptide’s antibacterial activity, while reducing its toxic potential is tested.
Abstract: Nowadays, the alarming rise in multidrug-resistant microorganisms urgently demands for suitable alternatives to current antibiotics. In this regard, antimicrobial peptides (AMPs) have received growing interest due to their broad spectrum of activities, potent antimicrobial properties, unique mechanisms of action and low tendency to induce resistance. However, their pharmaceutical development is hampered by potential toxicity, relatively low stability and manufacturing costs. In the present study, we tested the hypothesis that the encapsulation of the frog-skin derived AMP temporin B (TB) into chitosan nanoparticles (CS-NPs) could increase peptide’s antibacterial activity, while reducing its toxic potential. TB-loaded CS-NPs with good dimensional features were prepared, based on the ionotropic gelation between CS and sodium tripolyphosphate. The encapsulation efficiency of TB in the formulation was up to 75%. Release kinetic studies highlighted a linear release of the peptide from the nanocarrier, in the adopted experimental conditions. Interestingly, the encapsulation of TB in CS-NPs demonstrated to reduce significantly the peptide’s cytotoxicity against mammalian cells. Additionally, the nanocarrier evidenced a sustained antibacterial action against various strains of Staphylococcus epidermidis for at least 4 days, with up to 4-log reduction in the number of viable bacteria compared to plain CS-NPs at the end of the observational period. Of note, the antimicrobial evaluation tests demonstrated that while the intrinsic antimicrobial activity of CS ensured a “burst” effect, the gradual release of TB further reduced the viable bacterial count, preventing the regrowth of the residual cells and ensuring a long-lasting antibacterial effect. The developed nanocarrier is eligible for the administration of several AMPs of therapeutic interest with physical-chemical characteristics analogue to those of TB.
TL;DR: This high-resolution structure of the oncocin derivative Onc112 bound to the Thermus thermophilus 70S ribosome reveals the mechanism by which onc Cocins inhibit protein synthesis, providing an opportunity for structure-based design of new-generation therapeutics.
Abstract: Antibiotic-resistant bacteria are a global health issue necessitating the development of new effective therapeutics. Proline-rich antimicrobial peptides (PrAMPs), which include oncocins, are an extensively studied class of AMPs that counteract bacterial infection at submicromolar concentrations. Oncocins enter and kill bacteria by inhibiting certain targets rather than by acting through membrane lysis. Although they have recently been reported to bind DnaK and the bacterial ribosome, their mode of inhibition has remained elusive. Here we report the crystal structure of the oncocin derivative Onc112 bound to the Thermus thermophilus 70S ribosome. Strikingly, this 19-residue proline-rich peptide manifests the features of several known classes of ribosome inhibitors by simultaneously blocking the peptidyl transferase center and the peptide-exit tunnel of the ribosome. This high-resolution structure thus reveals the mechanism by which oncocins inhibit protein synthesis, providing an opportunity for structure-based design of new-generation therapeutics.
TL;DR: The findings from analyzing LPS mutant strains suggest that the core oligosaccharide of the LPS molecule is not essential for the antimicrobial activity of cationic AMPs, but in fact has a protective role against AMPs.
Abstract: Analysis of a Selected Set of Antimicrobial Peptides The rapid emergence of resistance to classical antibiotics has increased the interest in novel antimicrobial compounds. Antimicrobial peptides (AMPs) represent an attractive alternative to classical antibiotics and a number of different studies have reported antimicrobial activity data of various AMPs, but there is only limited comparative data available. The mode of action for many AMPs is largely unknown even though several models have suggested that the lipopolysaccharides (LPS) play a crucial role in the attraction and attachment of the AMP to the bacterial membrane in Gram-negative bacteria. We compared the potency of Cap18, Cap11, Cap11-1-18m2, Cecropin P1, Cecropin B, Bac2A, Bac2A-NH2, Sub5-NH2, Indolicidin, Melittin, Myxinidin, Myxinidin-NH2, Pyrrhocoricin, Apidaecin and Metalnikowin I towards Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, Aeromonas salmonicida, Listeria monocytogenes, Campylobacter jejuni, Flavobacterium psychrophilum, Salmonella typhimurium and Yersinia ruckeri by minimal inhibitory concentration (MIC) determinations. Additional characteristics such as cytotoxicity, thermo and protease stability were measured and compared among the different peptides. Further, the antimicrobial activity of a selection of cationic AMPs was investigated in various E. coli LPS mutants. Cap18 Shows a High Broad Spectrum Antimicrobial Activity Of all the tested AMPs, Cap18 showed the most efficient antimicrobial activity, in particular against Gram-negative bacteria. In addition, Cap18 is highly thermostable and showed no cytotoxic effect in a hemolytic assay, measured at the concentration used. However, Cap18 is, as most of the tested AMPs, sensitive to proteolytic digestion in vitro. Thus, Cap18 is an excellent candidate for further development into practical use; however, modifications that should reduce the protease sensitivity would be needed. In addition, our findings from analyzing LPS mutant strains suggest that the core oligosaccharide of the LPS molecule is not essential for the antimicrobial activity of cationic AMPs, but in fact has a protective role against AMPs.
TL;DR: This review outlines selected anion and cationic AMPs which are at various stages of development, from preliminary analysis to clinical drug development, and considers current production methods and delivery tools for AMPs, which must be improved for the effective use of these agents.
TL;DR: The role and significance of cathelicidins in inflammation and innate immunity against pathogens is discussed and various immunomodulatory activities of these peptides are indicated.
Abstract: Cathelicidins, like other antimicrobial peptides, exhibit direct antimicrobial activities against a broad spectrum of microbes, including both Gram-positive and Gram-negative bacteria, enveloped viruses, and fungi. These host-derived peptides kill the invaded pathogens by perturbing their cell membranes and can neutralize biological activities of endotoxin. Nowadays, more and more data indicate that these peptides, in addition to their antimicrobial properties, possess various immunomodulatory activities. Cathelicidins have the potential to influence and modulate, both directly and indirectly, the activity of various cell populations involved in inflammatory processes and in host defense against invading pathogens. They induce migration of neutrophils, monocytes/macrophages, eosinophils, and mast cells and prolong the lifespan of neutrophils. These peptides directly activate inflammatory cells to production and release of different pro-inflammatory and immunoregulatory mediators, cytokines, and chemokines, however cathelicidins might mediate the generation of anti-inflammatory cytokines as well. Cathelicidins also modulate epithelial cell/keratinocyte responses to infecting pathogens. What is more, they affect activity of monocytes, dendritic cells, keratinocytes, or epithelial cells acting in synergy with cytokines or β-defensins. In addition, these peptides indirectly balance TLR-mediated responses of monocytes, macrophages, dendritic cells, epithelial cells, and keratinocytes. This review discusses the role and significance of cathelicidins in inflammation and innate immunity against pathogens.
TL;DR: Multiple strategies by which bacteria could develop enhanced antimicrobial peptide resistance are discussed, focusing on sub-cellular regions from the surface to deep inside, evaluating bacterial membranes, cell walls and cytoplasmic metabolism.
TL;DR: The sequence diversity of invertebrate AMPs (defensins, cecropins, crustins and anti-lipopolysaccharide factors) are presented to provide a better understanding of the evolution pattern of these peptides that play a major role in host defense mechanisms.
Abstract: Antimicrobial peptides (AMPs) are evolutionarily ancient molecules that act as the key components in the invertebrate innate immunity against invading pathogens. Several AMPs have been identified and characterized in invertebrates, and found to display considerable diversity in their amino acid sequence, structure and biological activity. AMP genes appear to have rapidly evolved, which might have arisen from the co-evolutionary arms race between host and pathogens, and enabled organisms to survive in different microbial environments. Here, the sequence diversity of invertebrate AMPs (defensins, cecropins, crustins and anti-lipopolysaccharide factors) are presented to provide a better understanding of the evolution pattern of these peptides that play a major role in host defense mechanisms.
TL;DR: This is the first molecular dynamics simulation study of the interaction of the antimicrobial peptide, polymyxin B1 with complex models of both the inner and outer membranes of E. coli, and reveals key mechanistic details that may be exploited for future rational drug development.
Abstract: Antimicrobial peptides are small, cationic proteins that can induce lysis of bacterial cells through interaction with their membranes. Different mechanisms for cell lysis have been proposed, but these models tend to neglect the role of the chemical composition of the membrane, which differs between bacterial species and can be heterogeneous even within a single cell. Moreover, the cell envelope of Gram-negative bacteria such as E. coli contains two membranes with differing compositions. To this end, we report the first molecular dynamics simulation study of the interaction of the antimicrobial peptide, polymyxin B1 with complex models of both the inner and outer membranes of E. coli. The results of >16 microseconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms. The lipopeptides aggregate in the lipopolysaccharide headgroup region of the outer membrane with limited tendency for insertion within the lipid A tails. In contrast, the lipopeptides readily insert into the inner membrane core, and the concomitant increased hydration may be responsible for bilayer destabilization and antimicrobial function. Given the urgent need to develop novel, potent antibiotics, the results presented here reveal key mechanistic details that may be exploited for future rational drug development.
TL;DR: The potentiating functional interaction of co-occurring insect AMPs (the bumblebee linear peptides hymenoptaecin and abaecin) resulting in more potent antimicrobial effects at low concentrations suggest that combinations of AMPs could be used therapeutically against Gram-negative bacterial pathogens that have acquired resistance to common antibiotics.
Abstract: Antimicrobial peptides (AMPs) and proteins are important components of innate immunity against pathogens in insects. The production of AMPs is costly owing to resource-based trade-offs, and strategies maximizing the efficacy of AMPs at low concentrations are therefore likely to be advantageous. Here, we show the potentiating functional interaction of co-occurring insect AMPs (the bumblebee linear peptides hymenoptaecin and abaecin) resulting in more potent antimicrobial effects at low concentrations. Abaecin displayed no detectable activity against Escherichia coli when tested alone at concentrations of up to 200 μM, whereas hymenoptaecin affected bacterial cell growth and viability but only at concentrations greater than 2 μM. In combination, as little as 1.25 μM abaecin enhanced the bactericidal effects of hymenoptaecin. To understand these potentiating functional interactions, we investigated their mechanisms of action using atomic force microscopy and fluorescence resonance energy transfer-based quenching assays. Abaecin was found to reduce the minimal inhibitory concentration of hymenoptaecin and to interact with the bacterial chaperone DnaK (an evolutionarily conserved central organizer of the bacterial chaperone network) when the membrane was compromised by hymenoptaecin. These naturally occurring potentiating interactions suggest that combinations of AMPs could be used therapeutically against Gram-negative bacterial pathogens that have acquired resistance to common antibiotics.
TL;DR: A universal classification scheme is proposed herein to unify innate immunity peptides from a variety of biological sources and makes predictions based on the database-defined parameter space and provides a list of the sequences most similar to natural AMPs.
Abstract: Peptides with diverse amino acid sequences, structures, and functions are essential players in biological systems. The construction of well-annotated databases not only facilitates effective information management, search, and mining but also lays the foundation for developing and testing new peptide algorithms and machines. The antimicrobial peptide database (APD) is an original construction in terms of both database design and peptide entries. The host defense antimicrobial peptides (AMPs) registered in the APD cover the five kingdoms (bacteria, protists, fungi, plants, and animals) or three domains of life (bacteria, archaea, and eukaryota). This comprehensive database ( http://aps.unmc.edu/AP ) provides useful information on peptide discovery timeline, nomenclature, classification, glossary, calculation tools, and statistics. The APD enables effective search, prediction, and design of peptides with antibacterial, antiviral, antifungal, antiparasitic, insecticidal, spermicidal, anticancer activities, chemotactic, immune modulation, or antioxidative properties. A universal classification scheme is proposed herein to unify innate immunity peptides from a variety of biological sources. As an improvement, the upgraded APD makes predictions based on the database-defined parameter space and provides a list of the sequences most similar to natural AMPs. In addition, the powerful pipeline design of the database search engine laid a solid basis for designing novel antimicrobials to combat resistant superbugs, viruses, fungi, or parasites. This comprehensive AMP database is a useful tool for both research and education.
TL;DR: The traditional role for AMPs as being purely antimicrobial into question is called into question and an alternative scenario is proposed to assist neuroactive peptides in their antipredator role through their cytolytic action increasing the delivery of the latter to the endocrine and nervous system of the predator.
TL;DR: The association between AMPs and cancer with a focus on anticancer peptide functions and selectivity is described in an effort to understand potential therapeutic implications.
Abstract: Antimicrobial peptides (AMPs) play a critical role in innate host defense against microbial pathogens in many organisms. The human cathelicidin, LL-37, has a net positive charge and is amphiphilic, and can eliminate pathogenic microbes directly via electrostatic attraction toward negatively charged bacterial membranes. A number of studies have shown that LL-37 participates in various host immune systems, such as inflammatory responses and tissue repair, in addition to its antibacterial properties. Moreover, recent evidence suggests that it is also involved in the regulation of cancer. Indeed, previous studies have suggested that human LL-37 is involved in carcinogenesis via multiple reporters, such as FPR2 (FPRL1), epidermal growth factor receptor, and ERBb2, although LL-37 and its fragments and analogs also show anticancer effects in various cancer cell lines. This discrepancy can be attributed to peptide-based factors, host membrane-based factors, and signal regulation. Here, we describe the association between AMPs and cancer with a focus on anticancer peptide functions and selectivity in an effort to understand potential therapeutic implications.