RSSPerturbing the oxidizing environment of the periplasm stimulates the PhoQ/PhoP system in E. coli.
Source
Department of Biology, University of Pennsylvania, 433 S. University Ave Philadelphia, PA 19104-6018.
Abstract
The PhoQ/PhoP two-component system is repressed by divalent cations such as Mg(2+) and Ca(2+) in the growth medium and stimulated by low pH, and certain cationic antimicrobial peptides. In E. coli, it has recently been shown that the histidine kinase PhoQ is also modulated by at least two additional factors, the small membrane proteins SafA and MgrB. This raises the possibility that the PhoQ/PhoP circuit has additional regulatory components and integrates additional input signals. We screened E. coli transposon insertion mutants to look for proteins that modulate the activity of the PhoQ/PhoP system and uncovered a role for DsbA, a periplasmic oxidant that facilitates the formation of disulfide bonds. Deletion of dsbA or dsbB, which maintains a pool of oxidized DsbA, leads to increased transcription of at least two PhoP-regulated genes. Addition of the reducing agent DTT to wild-type cells has a similar effect and treatment of a dsbA null strain with the oxidant Cu(2+)rescues the reporter gene expression phenotype. We also demonstrate that expression of an MgrB mutant that lacks cysteines blocks the effect of a dsbA null mutation on PhoQ/PhoP activity, suggesting that MgrB acts downstream of DsbA in this pathway. Taken together, these results demonstrate that a decrease in the oxidizing activity of the periplasm stimulates PhoQ/PhoP and may reveal a new input stimulus for this important two-component system.
JBIR-78 and JBIR-95: Phenylacetylated Peptides Isolated from Kibdelosporangium sp. AK-AA56.
Source
Biomedicinal Information Research Center (BIRC), Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Abstract
The search for metabolites of Kibdelosporangium sp. AK-AA56 resulted in the discovery of novel N-phenylacetylatedpeptides, JBIR-78 (1) and JBIR-95 (2). Compounds 1 and 2 were established to be N-phenylacetylated heptapeptides by extensive NMR and HRESIMS analyses. The absolute configuration of the standard amino acids including a cysteic acid moiety was determined using Marfey's method on the acid hydrolysates of 1 and 2. The relative and absolute configurations of a nonstandard amino acid, β-hydroxyleucine, were elucidated using the J-based and modified Mosher's methods, respectively. In an antimicrobial test, 1 showed antibacterial activity against Micrococcus luteus.
QSAR Modeling and Design of Cationic Antimicrobial Peptides Based on Structural Properties of Amino Acids.
Source
College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400050, P.R. China. zhlin@cqut.edu.cn.
Abstract
Drug resistance to existing antibiotics poses alarming threats to global public health, which inspires heightened interests in searching for new antibiotics, including antimicrobial peptides (AMPs). Accurate prediction of antibacterial activities of AMPs may expedite novel AMP design and reduce the costs and efforts involved in laboratory screening. In the present study, a novel quantitative prediction method of AMP was established by quantitative structure-activity relationship (QSAR) modeling based on the physicochemical properties of amino acids. The indices of these physicochemical properties were used to define AMP. The structural variables were optimized by stepwise regression (STR). Three series of AMPs from the QSAR model were constructed by multiple linear regressions (MLR). These QSAR models showed good performance in reliability and predictability. The normalized regression coefficients of the QSAR model and the contribution of amino acids at each position of AMP may determine the suitableness of a particular residue at any given position. QSAR models constructed by STR-MLR should prove to be useful tools in peptide design with respect to the calculation, explanation, good and reliable performance, and definition of physiochemical properties.
- PMID:
- 22263858
- [PubMed - as supplied by publisher]
Roles of tRNA in cell wall biosynthesis.
Source
Department of Microbiology, Ohio State University, Columbus, OH, USA.
Abstract
Recent research into various aspects of bacterial metabolism such as cell wall and antibiotic synthesis, degradation pathways, cellular stress, and amino acid biosynthesis has elucidated roles of aminoacyl-transfer ribonucleic acid (aa-tRNA) outside of translation. Although the two enzyme families responsible for cell wall modifications, aminoacyl-phosphatidylglycerol synthases (aaPGSs) and Fem, were discovered some time ago, they have recently become of intense interest for their roles in the antimicrobial resistance of pathogenic microorganisms. The addition of positively charged amino acids to phosphatidylglycerol (PG) by aaPGSs neutralizes the lipid bilayer making the bacteria less susceptible to positively charged antimicrobial agents. Fem transferases utilize aa-tRNA to form peptide bridges that link strands of peptidoglycan. These bridges vary among the bacterial species in which they are present and play a role in resistance to antibiotics that target the cell wall. Additionally, the formation of truncated peptides results in shorter peptide bridges and loss of branched linkages which makes bacteria more susceptible to antimicrobials. A greater understanding of the structure and substrate specificity of this diverse enzymatic family is necessary to aid current efforts in designing potential bactericidal agents. These two enzyme families are linked only by the substrate with which they modify the cell wall, aa-tRNA; their structure, cell wall modification processes and the physiological changes they impart on the bacterium differ greatly. WIREs RNA 2012. doi: 10.1002/wrna.1108 For further resources related to this article, please visit the WIREs website.
Copyright © 2012 John Wiley & Sons, Ltd.
Activity, Expression and Genetic Variation of Canine β-Defensin 103: A Multifunctional Antimicrobial Peptide in the Skin of Domestic Dogs.
Source
Department of Microbiology and Immunology, UC Davis School of Medicine, Davis, Calif., USA.
Abstract
The skin functions as more than a physical barrier to infection. Epithelial cells of the skin can synthesize antimicrobialpeptides, including defensins, which exhibit direct antimicrobial activity. Here we characterize the expression pattern, genetic variation and activity of the major β-defensin expressed in canine skin, canine β-defensin 103 (CBD103). The gene encoding CBD103 exhibits two forms of polymorphism: a common 3-basepair deletion allele and a gene copy-number variation. Golden retrievers and Labrador retrievers were the only breeds that encoded the variant allele of CBD103, termed CBD103ΔG23. Both these breeds also exhibited a CBD103 gene copy-number polymorphism that ranged from 2 to 4 gene-copies per diploid genome. Recombinant CBD103 and CBD103ΔG23, as well as the human ortholog human β-defensin 3 (hBD3) and hBD3ΔG23, showed potent and comparable antimicrobial killing against both methicillin-susceptible and methicillin-resistant Staphylococcus pseudintermedius. Skin biopsy specimens from dogs with atopic dermatitis revealed CBD103 expression levels similar to those in healthy controls and comparable at lesional and nonlesional sites. This expression pattern in dogs differs from the previously reported reduced expression of the human ortholog in atopic dermatitis. Overall, the similarities of CBD103 and its human ortholog reported here support the notion that the domestic dog may serve as a valuable model for studying β-defensin biology in the skin.
Copyright © 2012 S. Karger AG, Basel.
The importance of the cell membrane on the mechanism of action of cyclotides.
Abstract
Their distinctive structures, diverse range of bioactivities, and potential for pharmaceutical or agricultural applications make cyclotides an intriguing family of cyclic peptides. Together with the physiological role in plant host defence, cyclotides possess antimicrobial, anticancer and anti-HIV activities. In all of the reported activities, cell membranes seem to be the primary target for cyclotide binding. This article examines recent literature on cyclotide-membrane studies and highlights the hypothesis that the activity of cyclotides is dependent on their affinity for lipid bilayers and enhanced by the presence of specific lipids, i.e., phospholipids containing phosphatidylethanolamine headgroups. There is growing evidence that the lipid composition of target cell membranes dictates the amount of cyclotides bound to the cell and the extent of their activity. After membrane targeting and insertion in the bilayer core, cyclotides induce disruption of membranes by a pore formation mechanism. This proposed mechanism of action is supported by biophysical studies with model membranes and by studies on natural biological membranes of known lipid compositions.
[Research progress in fusion expression of antimicrobial peptides].
Source
Laboratory of Feed Biotechnology, State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China.
Abstract
Antimicrobial peptides (AMPs) are of great significance in the field of food, feed and medicine due to their wide spectrum of antimicrobial activity and new mechanism of action different from conventional antibiotics. AMPs production from natural sources is usually limited, and chemical synthesis is not economically practical, especially for the production of long peptides. Therefore, heterologous expression of AMPs has been widely studied as an alternative, and fusion expression plays an important role in increasing production. The present review mainly focuses on the types and bioactivities of AMPs. In addition, the recent strategies to the most commonly used carrier proteins for fusion expression of AMPs and prospects for future research were also discussed.
- PMID:
- 22260057
- [PubMed - in process]
Antimicrobial implications of vitamin D.
Source
Mountain Home VAMC Medicine Service; Mountain Home; TN USA.
Abstract
Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobialproperties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.
Infection of honey bees with acute bee paralysis virus does not trigger humoral or cellular immune responses.
Source
BEEgroup, Biocentre, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
Abstract
We have studied the responses of honey bees at different life stages (Apis mellifera) to controlled infection with acute bee paralysis virus and have identified the haemolymph of infected larvae and adult worker bees as the compartment where massive propagation of ABPV occurs. Insects respond with a broad spectrum of induced innate immune reactions to bacterial infections, whereas defence mechanisms based on RNA interference play a major role in antiviral immunity. In this study, we have determined that honey bee larvae and adult workers do not produce a humoral immune reaction upon artificial infection with ABPV, in contrast to control individuals challenged with Escherichia coli. ABPV-infected bees produced neither elevated levels of specific antimicrobial peptides (AMPs), such as hymenoptaecin and defensin, nor any general antimicrobial activity, as revealed by inhibition-zone assays. Additionally, adult bees did not generate melanised nodules upon ABPV infection, an important cellular immune function activated by bacteria and viruses in some insects. Challenge of bees with both ABPV and E. coli showed that innate humoral and cellular immune reactions are induced in mixed infections, albeit at a reduced level.
Production, purification, and characterization of the cecropin from Plutella xylostella, pxCECA1, using an intein-induced self-cleavable system in Escherichia coli.
Source
State Key Laboratory of Virology, College of Life Science, Wuhan University, Wuhan, 430072, People's Republic of China.
Abstract
Antimicrobial peptides (AMPs) are widely expressed and play an important role in innate immune defense against infectious agents such as bacteria, viruses, fungi, and parasites. Cecropins are a family of AMPs synthesized in the fat body of insects that have proven effective at killing specific pathogens. In order to fulfill their clinical potential asantimicrobial drugs, a simple, cost-effective method to express AMPs is sorely needed. In this study, we expressed and characterized the cecropin from Plutella xylostella (pxCECA1) using an intein-dependent expression system in Escherichia coli. We cloned the pxCECA1 gene from larva by RT-PCR and fused the encoding sequence of mature pxCECA1 with an intein gene and a chitin-binding domain gene (CBD) in pTWIN1 plasmid. The fusion protein CBD-intein-pxCECA1 was expressed in E. coli BL21 (DE3) and separated by flowing cell extracts through a chitin column. Subsequently, self-cleavage of the intein at its C-terminus was induced in a temperature- and pH-dependent manner, resulting in the release of mature pxCECA1. The optimal conditions for self-cleavage were determined to be pH 6.0 for 48 h at 4°C, under which 12.3 mg of recombinant pxCECA1 could be recovered from 1 l of E. coli culture. The purified pxCECA1 displayed antimicrobial activity against a broad variety of gram-positive and gram-negative bacteria. This preparation was especially effective against Staphylococcus aureus, including methicillin-resistant strains. Catalase release assays demonstrated that pxCECA1 acts as a microbicidal agent. These results show for the first time that the IMPACT-TWIN expression system is an efficient, cost-effective way to produce fully functional AMPs and that the AMP pxCECA1 is a novel microbicidal agent with promising therapeutic applications.
The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila.
Source
Department of Neurobiology and Behavior, Columbia University Medical School, New York, New York, United States of America.
Abstract
Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim) and Period (Per) are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load) or tolerance (endurance of the pathogenic effects of infection). Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim-independent; moreover, infection-induced AMP gene expression is not circadian-regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis) can have significant effects on long-term survival of infection.
Roles of Hydrophobicity and Charge Distribution of Cationic AntimicrobialPeptides in Peptide-Membrane Interactions.
Source
Hospital for Sick Children, Toronto, Canada;
Abstract
Cationic antimicrobial peptides (CAPs) occur as important innate immunity agents in many organisms (including humans) and offer a viable alternative to conventional antibiotics as they physically disrupt the bacterial membranes, leading to membrane lysis and eventually cell death. In the present work, we studied the biophysical and microbiological characteristics of designed CAPs varying in hydrophobicity levels and charge distributions by a variety of biophysical and biochemical approaches, including in tandem atomic force microscopy (AFM) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), circular dichroism spectroscopy, and SDS-PAGE. Peptide structural properties were correlated with their membrane disruptive powers and antimicrobial activities. In bacterial lipid model membranes, a time-dependent increase of aggregated beta-strand-type structure in CAPs with relatively high hydrophobicity (such as KKKKKK-ALFALWLAFLA-NH2) was essentially absent in CAPs with lower hydrophobicity (such as KKKKKK-AAFAAWAAFAA-NH2). Re-distribution of positive charges by placing three Lys residues at both termini while maintaining identical sequences minimized self-aggregation above the dimer level. Peptides containing four Leu residues were destructive to mammalian model membranes, while those with corresponding Ala residues were not. This finding was mirrored in hemolysis studies in human erythrocytes, where Ala-only peptides displayed virtually no hemolysis up to 320 μM, but the four-Leu peptides induced 40-80% hemolysis in the same concentration range. Allpeptides studied displayed strong antimicrobial activity against Pseudomonas aeruginosa (MICs = 4-32 μM). The overall findings suggest optimal routes to balancing peptide hydrophobicity and charge distribution that allow efficient penetration and disruption of the bacterial membranes without damage to mammalian (host) membranes.
Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell-envelope active antibiotics.
Source
Department of Biology, Texas Christian University, Fort Worth, TX 76129.
Abstract
The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobialpeptides and antibiotics that target the cell well and/or cell membrane such as penicillin and daptomycin in B. anthracis and drug resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.
Identification, synthesis and characterization of a novel antimicrobial peptide HKPLP derived from Hippocampus kuda Bleeker.
Source
State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, National Engineering Research Center of South China Sea Marine Biotechnology, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Abstract
A novel gene encoding 55 amino-acid residues has been identified from the brooding pouch cDNA library of Hippocampus kuda Bleeker. The deduced amino-acid sequence is highly homologous to several pleurocidin-likepeptides from the winter flounder and comprises a signal peptide, a pro-peptide and a mature peptide. The glycine-rich mature peptide, designated HKPLP, contains 24 amino-acid residues and has been synthesized by solid-phase peptide synthesis. The purified HKPLP exhibits antimicrobial activity against several Gram-positive and Gram-negative bacterial strains at low concentrations (MIC 1.5-7.5 μM). Thermal stability assay data show good heat stability. CD spectroscopy experiments indicate that the dominant contents are anti-parallel and parallel sheets, which may have β-sheet or β-strand motif. It is inferred that HKPLP participates in the host defense during egg fertilization and embryo development as an antimicrobial peptide in brooding pouch.The Journal of Antibiotics advance online publication, 18 January 2012; doi:10.1038/ja.2011.120.
Inhibition of microorganisms on a carrion breeding resource: the antimicrobialPeptide activity of burying beetle (coleoptera: silphidae) oral and anal secretions.
Source
Department of Biological Sciences, Idaho State University, 921 S. 8th Ave. Stop 8007, Pocatello, ID 83209, USA.
Abstract
Competition between scavengers and microorganisms for the nutrients within carrion is well documented. As a significant contributor to food web energetics, carrion serves not only as a food source for scavengers, but also as a reproductive resource for many insects. One example are the burying beetles of the Nicrophorus genus (Coleoptera: Silphidae) whose reproduction is dependent on locating and successfully sequestering vertebrate carrion. Throughout the cooperative preparation of carrion and feeding of the larval offspring, parental beetles coat the carrion with oral and anal secretions known to attenuate the growth of molds and bacteria in the laboratory. We test the hypotheses that Nicrophorus secretions attenuate the growth of naturally occurring microorganisms likely to be found colonizing the carrion resource, and that the active antimicrobial components of the secretions are small antimicrobial peptides(AMPs) similar to those produced by other insects.
- PMID:
- 22251646
- [PubMed - in process]
Antimicrobial activity of peptides derived from human ß-amyloid precursor protein.
Source
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84, Lund, Sweden.
Abstract
Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptidesderived from the heparin-binding disulfide-constrained loop region of human ß-amyloid precursor protein areantimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptidespermeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic activities within the concentration range investigated and exerted very small membrane permeabilising effects on human epithelial cells. The efficiency of the peptides with respect to bacterial killing and liposome membrane leakage was in the order NWC20c > NWC15c > NWC15l, which also correlated to the adsorption density for these peptides at the model lipid membrane. Thus, whereas the cationic sequence is a minimum determinant for antimicrobial action, a constrained loop-structure as well as a hydrophobic extension further contributes to membrane permeabilising activity of this region of amyloid precursor protein. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Synthesis of anticancer heptapeptides containing a unique lipophilic β(2,2) -amino acid building block.
Source
Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, NO-9037, Tromsø, Norway.
Abstract
We report a series of synthetic anticancer heptapeptides (H-KKWβ(2,2) WKK-NH(2) ) containing eight different central lipophilic β(2,2) -amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC(50) values of 9-23 µm against human Burkitt's lymphoma and murine B-cell lymphoma and were all nonhaemolytic (EC(50) > 200 µm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Extensive manipulation of caseicin A and B highlighting the tolerance of theseantimicrobial peptides to change.
Source
Microbiology Department, University College Cork, Cork, Ireland.
Abstract
Caseicin A and B are low molecular weight antimicrobial peptides which are released by proteolytic digestion of sodium caseinate. Caseicin A (IKHQGLPQE) is a nine amino acid, cationic peptide and Caseicin B (VLNENLLR) is a neutral eight amino acid peptide, both of which have previously been shown to exhibit antibacterial activity against a number of pathogens including Cronobacter sakazakii. Previously, four variants of each of caseicin which differed subtly from their natural counterparts were generated by peptide synthesis. Antimicrobial activity assays in this study revealed that the importance of a number of the residues within the peptides was dependent on the strain being targeted. Here this engineering-based approach is expanded on through the creation of a larger collection of 26 peptides which are altered in a variety of ways. The investigation highlighted the generally greater tolerance of caseicin B to change, the fact that changes have a more detrimental impact on anti-Gram negative activity and the surprising number of variants which exhibit enhanced activity against S. aureus.
The role of the Src family kinase Lyn in the immunomodulatory activities of cathelicidin peptide LL-37 on monocytic cells.
Source
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Abstract
Cathelicidin LL-37 is a multifunctional, immunomodulatory and antimicrobial host-defense peptide of the human immune system. Here, we identified the role of SFKs in mediating the chemokine induction activity of LL-37 in monocytic cells. LL-37 induced SFK phosphorylation; and chemical inhibitors of SFKs suppressed chemokine production in response to LL-37 stimulation. SFKs were required for the downstream activation of AKT, but Ca(2+)-flux and MAPK induction were SFK-independent. Through systematic siRNA knockdown of SFK members, a requirement for Lyn in mediating LL-37 activity was identified. The involvement of Lyn in cathelicidin activities was further confirmed using Lyn-knockout mouse BMDMs. The role of SFKs and Lyn was also demonstrated in the activities of the synthetic cationic IDR peptides, developed as novel, immunomodulatory therapeutics. These findings elucidate the common molecular mechanisms mediating the chemokine induction activity of natural and synthetic cationic peptides in monocytic cells and identify SFKs as a potential target for modulating peptide responses.
Role of lipids in the interaction of antimicrobial peptides with membranes.
Source
CIQ(UP), Departamento de Química e Bioquímica, FCUP, R. do Campo Alegre, Porto 4169-007, Portugal; REQUIMTE, Departamento de Química e Bioquímica, FCUP, R. do Campo Alegre, Porto 4169-007, Portugal.
Abstract
Antimicrobial peptides (AMPs) take part in the immune system by mounting a first line of defense against pathogens. Recurrent structural and functional aspects are observed among peptides from different sources, particularly the net cationicity and amphipathicity. However, the membrane seems to be the key determinant of their action, either as the main target of the peptide action or by forming a barrier that must be crossed by peptides to target core metabolic pathways. More importantly, the specificity exhibited by antimicrobial peptides relies on the different lipid composition between pathogen and host cells, likely contributing to their spectrum of activity. Several mechanisms of action have been reported, which may involve membrane permeabilization through the formation of pores, membrane thinning or micellization in a detergent-like way. AMPs may also target intracellular components, such as DNA, enzymes and even organelles. More recently, these peptides have been shown to produce membrane perturbation by formation of specific lipid-peptide domains, lateral phase segregation of zwitterionic from anionic phospholipids and even the formation of non-lamellar lipid phases. To countermeasure their activity, some pathogens were successful in developing effective mechanisms of resistance to decrease their susceptibility to AMPs. The functional and integral knowledge of such interactions and the clarification of the complex interplay between molecular determinants of peptides, the pathogen versus host cells dichotomy and the specific microenvironment in which all these elements convene will contribute to an understanding of some elusive aspects of their action and to rationally design novel therapeutic agents to overcome the current antibiotic resistance issue.
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