Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities.

Antimicrobial peptides (AMPs) are regarded as a new generation of antibiotics. Besides antimicrobial activity, AMPs also have antibiofilm, immune-regulatory, and other activities. Exploring the mechanism of action of AMPs may help in the modification and development of AMPs. Many studies were conducted on the mechanism of AMPs. The present review mainly summarizes the research status on the antimicrobial, anti-inflammatory, and antibiofilm properties of AMPs. This study not only describes the mechanism of cell wall action and membrane-targeting action but also includes the transmembrane mechanism of intracellular action and intracellular action targets. It also discusses the dual mechanism of action reported by a large number of investigations. Antibiofilm and anti-inflammatory mechanisms were described based on the formation of biofilms and inflammation. This study aims to provide a comprehensive review of the multiple activities and coordination of AMPs in vivo, and to fully understand AMPs to realize their therapeutic prospect.

New Role for Radical SAM Enzymes in the Biosynthesis of Thio(seleno)oxazole RiPP Natural Products.

Ribosomally synthesized post-translationally modified peptides (RiPPs) are ubiquitous and represent a structurally diverse class of natural products. The ribosomally encoded precursor polypeptides are often extensively modified post-translationally by enzymes that are encoded by coclustered genes. Radical S-adenosyl-l-methionine (SAM) enzymes catalyze numerous chemically challenging transformations. In RiPP biosynthetic pathways, these transformations include the formation of C-H, C-C, C-S, and C-O linkages. In this paper, we show that the Geobacter lovleyi sbtM gene encodes a radical SAM protein, SbtM, which catalyzes the cyclization of a Cys/SeCys residue in a minimal peptide substrate. Biochemical studies of this transformation support a mechanism involving H-atom abstraction at the C-3 of the substrate Cys to initiate the chemistry. Several possible cyclization products were considered. The collective biochemical, spectroscopic, mass spectral, and computational observations point to a thiooxazole as the product of the SbtM-catalyzed modification. To our knowledge, this is the first example of a radical SAM enzyme that catalyzes a transformation involving a SeCys-containing peptide and represents a new paradigm for formation of oxazole-containing RiPP natural products.

Ultraviolet radiation, vitamin D, and COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become pandemic on March 11th, 2020. COVID-19 has a range of symptoms that includes fever, fatigue, dry cough, aches, and labored breathing to acute respiratory distress and possibly death. Health systems and hospitals have been completely rearranged since March 2020 in order to limit the high rate of virus spreading. Hence, a great debate on deferrable visits and treatments including phototherapy for skin diseases is developing. In particular, as regards phototherapy very few data are currently available regarding the chance to continue it, even if it may be a useful resource for treating numerous dermatological patients. However, phototherapy has an immunosuppressive action possibly facilitating virus infection. In the context of COVID-19 infection risk it is important to pointed out whether sunlight, phototherapy and in particular ultraviolet radiation (UV-R) constitute or not a risk for patients. In this review we aimed to focus on the relationship between UV-R, sunlight, phototherapy, and viral infections particularly focusing on COVID-19.

Transgenic Mice Overexpressing PG1 Display Corneal Opacity and Severe Inflammation in the Eye.

Antimicrobial peptides (AMPs) are of interest as alternatives to antibiotics or immunomodulators. We generated and characterized the phenotypes of transgenic mice overexpressing protegrin 1 (PG1), a potent porcine cathelicidin. No obvious differences were observed between PG1 transgenic and wild-type mice in terms of growth, development, general behaviour, and the major immune cell population. However, PG1 transgenic mice intranasally infected with Staphylococcus aureus resulted in a reduction in microscopic pulmonary injury, improved clearance of bacteria, and lower proinflammatory cytokine secretion, compared to those of wild-type mice. On the other hand, approximately 25% of PG1 transgenic mice (n = 54/215) showed corneal opacity and developed inflammation in the eye, resulting ultimately in phthisis bulbi. Immunohistochemical analyses revealed that PG1 and its activator, neutrophil elastase, localized to the basal cells of the cornea and glands in eyelids, respectively. In addition, apoptosis indicated by a Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive signal was detected from flat cells of the cornea. Our study suggests that the expression regulation or localization of AMPs such as PG1 is important to prevent their adverse effects. However, our results also showed that the cytotoxic effects of PG1 on cells could be tolerated in animals, except for the eyes.

Identification of biomarkers for drug-resistant endometriosis using clinical proteomics.

Dienogest (DNG), is an effective and widely used progestin used in the treatment of endometriosis, yet clinically, a subset of cases show resistance to DNG treatment. During a previous investigation on the effect of DNG of cytokines and growth factor production, we incidentally found that endometriotic cyst fluid did not demonstrate inhibitory effects to DNG in a subset of cases. To clarify the mechanisms of this resistance to DNG, we performed proteomics analysis to compare the protein expression between DNG-sensitive and resistant cases. Based upon our results, several proteins were extracted that relate to neutrophil granulocyte activation marker (myeloperoxidase, lactotransferrin), inflammation (azurocidin, neutrophil gelatinase-associated lipocalin, etc.), and others biological processes reflecting the clinical environment of the endometriotic cyst. Among these proteins, azurocidin (AZU) is perhaps most interesting one as azurocidin is a protease that cleaves insulin-like growth factor-1 (IGFBP-1) associated with clear cell carcinoma of the ovary. We propose that the proteins extracted in the present study warrant further investigation in their relationship to carcinogenesis of endometrioma.

Advancing d-amino acid-containing peptide discovery in the metazoan.

The discovery of enzyme-derived d-amino acid-containing peptides (DAACPs) that have physiological importance in the metazoan challenges previous assumptions about the homochirality of animal proteins while simultaneously revealing new analytical challenges in the structural and functional characterization of peptides. Most known DAACPs have been identified though laborious activity-guided purification studies or by homology to previously identified DAACPs. Peptide characterization experiments are increasingly dominated by high throughput mass spectrometry-based peptidomics, with stereochemistry rarely considered due to the technical challenges of identifying l/d isomerization. This review discusses the prevalence of enzyme-derived DAACPs among animals and the physiological consequences of peptide isomerization. Also highlighted are the analytical methods that have been applied for structural characterization/discovery of DAACPs, including results of several recent studies using non-targeted discovery methods for revealing novel DAACPs, strongly suggesting that more DAACPs remain to be uncovered.

The role of azurocidin in patients with familial Mediterranean fever and AA amyloidosis and its association with cardiovascular risk factors.

BACKGROUND: Familial Mediterranean fever (FMF) is characterized by sporadic, recurrent attacks of fever and serosal inflammation. AA amyloidosis (AAA) is a disorder characterized by the extracellular tissue deposition of serum amyloid A protein (SAA). Azurocidin is a neutrophil-derived granule protein. We aimed to investigate the significance of azurocidin in FMF and AAA and the correlation between azurocidin levels and carotid artery intima media thickness (CA-IMT) and cardiovascular plaque existence. METHODS: A sum of 52 FMF patients were enrolled in the study. FMF patients were composed of two groups. Group-1 included 30 patients with non-complicated FMF. Group-2 included 22 patients whom received renal transplantation due to FMF complicated with AAA and being followed up at stable state for at least one year. 24 healthy individuals who matched with FMF patients in terms of age and gender consisted the control group. RESULTS: We found statistically significant difference between patient and control groups in terms of urea (38.52 ± 19.96 mg/dl vs 29.08 ± 5.83 mg/dl; p = 0.003), creatinine (1.11 ± 0.39 mg/dl vs 0.91 ± 0.16 mg/dl; p = 0.002), serum uric acid (6.2 ± 2 mg/dl vs 4.5 ± 0.9 mg/dl; p < 0.001), serum CRP (8.62 ± 9.5 mg/dl vs 3.91 ± 3.9 mg/dl; p = 0.004), ferritin (151.4 ± 317 ng/ml vs 33.3 ± 34 ng/ml; p = 0.014), white blood cell (WBC) levels (7.97 ± 2.3 × 103/µL vs 6.6 ± 1.7 × 103/µL; p = 0.018), serum azurocidin levels (137.16 ± 65.62 ng/ml vs 102.35 ± 51.61 ng/ml; p = 0.015) and mean CA-IMT (0.57 ± 0.15 mm vs 0.47 ± 0.07 mm; p = 0.001). Comparison of group 1 and group 2 revealed statistically significant differences in terms of urea (26 ± 8 mg/dl vs 54 ± 19 mg/dl; p < 0.001), creatinine (0.87 ± 0.1 mg/dl vs 1.44 ± 0.3 mg/dl; p < 0.001), estimated glomerular filtration rate (eGFR) (99 ± 21 ml/min/1.73m2 vs 53 ± 16 ml/min/1.73m2; p < .001), uric acid (4.9 ± 1.3 mg/dl vs 7.6 ± 1.7 mg/dl; p < 0.001), ferritin (31.7 ± 27 ng/ml vs 292.8 ± 431 ng/ml; p = 0.010) and albumin (4.5 ± 0.3 g/dl vs 4.1 ± 0.3 g/dl; p = 0.001). There was no statistically significant difference between group 1 and group 2 in terms of mean CA-IMT (CA-IMT (M) (mm): 0.54 ± 0.14 vs 0.62 ± 0.17, p = 0.057). Serum azurocidin levels were not significantly different between group 1 and group 2 (121.73 ± 53.24 ng/ml vs 158.19 ± 75.77 ng/ml; p = 0.061). In multivariate linear regression analysis (variables: MBP, urea, creatinine, eGFR, ferritin, uric acid, CA-IMT) azurocidin was independently associated with urea (t:2.658; p = 0.010) and CA-IMT (t:2.464; p = 0.017). DISCUSSION: Based on our findings, azurocidin seems to be a good inflammation marker in patients with FMF. Increase in azurocidin levels might be associated with development of amyloidosis. Also, serum azurocidin levels may be used as a predictor of both inflammatory state and cardiovascular risk, especially when used with other markers such as CA-IMT.

Overview of Host Defense Peptides and Their Applications for Plastic and Reconstructive Surgeons.

BACKGROUND: Host defense peptides are a family of endogenous short peptides that are found in all living beings and play a critical role in innate immunity against infection. METHODS: A nonsystematic review of host defense peptides was conducted with specific interest in properties and applications relevant to plastic and reconstructive surgery. RESULTS: In addition to their direct antimicrobial actions against pathogens, including multidrug-resistant bacteria, they also demonstrate important functions in immunomodulation, tumor cell lysis, and tissue regeneration. These properties have made them a topic of clinical interest for plastic surgeons because of their potential applications as novel antibiotics, wound healing medications, and cancer therapies. The rising clinical interest has led to a robust body of literature describing host defense peptides in great depth and breadth. Numerous mechanisms have been observed to explain their diverse functions, which rely on specific structural characteristics. However, these peptides remain mostly experimental, with limited translation to clinical practice because of numerous failures to achieve acceptable results in human trials. CONCLUSIONS: Despite the broad ranging potential of these peptides for use in the field of plastic and reconstructive surgery, they are rarely discussed in the literature or at scientific meetings. In this review, the authors provide a summary of the background, structure, function, bacterial resistance, and clinical applications of host defense peptides with the goal of stimulating host defense peptide-based innovation within the field of plastic and reconstructive surgery.

Functional Insights From the Evolutionary Diversification of Big Defensins.

Big defensins are antimicrobial polypeptides believed to be the ancestors of ß-defensins, the most evolutionary conserved family of host defense peptides (HDPs) in vertebrates. Nevertheless, big defensins underwent several independent gene loss events during animal evolution, being only retained in a limited number of phylogenetically distant invertebrates. Here, we explore the evolutionary history of this fascinating HDP family and investigate its patchy distribution in extant metazoans. We highlight the presence of big defensins in various classes of lophotrochozoans, as well as in a few arthropods and basal chordates (amphioxus), mostly adapted to life in marine environments. Bivalve mollusks often display an expanded repertoire of big defensin sequences, which appear to be the product of independent lineage-specific gene tandem duplications, followed by a rapid molecular diversification of newly acquired gene copies. This ongoing evolutionary process could underpin the simultaneous presence of canonical big defensins and non-canonical (ß-defensin-like) sequences in some species. The big defensin genes of mussels and oysters, two species target of in-depth studies, are subjected to gene presence/absence variation (PAV), i.e., they can be present or absent in the genomes of different individuals. Moreover, big defensins follow different patterns of gene expression within a given species and respond differently to microbial challenges, suggesting functional divergence. Consistently, current structural data show that big defensin sequence diversity affects the 3D structure and biophysical properties of these polypeptides. We discuss here the role of the N-terminal hydrophobic domain, lost during evolution toward ß-defensins, in the big defensin stability to high salt concentrations and its mechanism of action. Finally, we discuss the potential of big defensins as markers for animal health and for the nature-based design of novel therapeutics active at high salt concentrations.

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis.

OBJECTIVES: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated. DESIGN: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp+/+) and knockout (Cnlp-/-) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. RESULTS: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms. CONCLUSIONS: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

The antimicrobial peptide maculatin self assembles in parallel to form a pore in phospholipid bilayers.

Little is known experimentally about the detailed orientation of membrane-bound maculatin 1.1 (Mac1), an antimicrobial peptide from the skin secretions of Australian tree frogs. In this work multiple 15N-labelled or 2H-labelled Mac1 with dodecylphosphocholine (DPC) micelles and isotropic DMPC/DHPC (q = 0.5) bicelles were investigated by solution NMR, circular dichroism (CD) spectroscopy, neutron reflectometry and molecular dynamics (MD) simulations in explicit solvent. In buffer, the 15N-1H HSQC and CD spectra were indicative of the peptide being random coiled. In the presence of micelles or isotropic bicelles, a unique and helical peptide structure that was confirmed by CD was found. The titration of the soluble paramagnetic agent gadolinium (Gd-DTPA) into the Mac1-DPC solution led to enhanced relaxation of all 15N labelled residues. The peptide N-terminus was more exposed to Gd-DTPA than the C-terminus in micelles, while only the Gly-4 and Ala-18 resonances were significantly reduced in the presence of isotropic bicelles. MD simulations of Mac1 fully inserted into a DPC micelle converged towards a solvent exposed orientation and a topology where Mac1 was wrapped around the DPC micelle with the more hydrophobic side facing inward. MD simulations of Mac1 fully inserted into a phosphatidylcholine (PC) bilayer converged towards a kinked transmembrane orientation with water molecules penetrating around Lys-8. A deuterium labelled Mac1 used in neutron reflectometry experiments suggested a preferred orientation in zwitterionic PC bilayers. These results give insight into the membrane disrupting activity of Mac1 against cell membranes.

The Role of Macrophages in Staphylococcus aureus Infection.

Staphylococcus aureus is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of serious diseases. This requires an ability to circumvent the innate immune system to establish an infection. Professional phagocytes, primarily macrophages and neutrophils, are key innate immune cells which interact with S. aureus, acting as gatekeepers to contain and resolve infection. Recent studies have highlighted the important roles of macrophages during S. aureus infections, using a wide array of killing mechanisms. In defense, S. aureus has evolved multiple strategies to survive within, manipulate and escape from macrophages, allowing them to not only subvert but also exploit this key element of our immune system. Macrophage-S. aureus interactions are multifaceted and have direct roles in infection outcome. In depth understanding of these host-pathogen interactions may be useful for future therapeutic developments. This review examines macrophage interactions with S. aureus throughout all stages of infection, with special emphasis on mechanisms that determine infection outcome.

Gastrointestinal Immunity and Alpha-Synuclein.

The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease.

Current understanding of the gut microbiota shaping mechanisms.

Increasing evidences have shown strong associations between gut microbiota and many human diseases, and understanding the dynamic crosstalks of host-microbe interaction in the gut has become necessary for the detection, prevention, or therapy of diseases. Many reports have showed that diet, nutrient, pharmacologic factors and many other stimuli play dominant roles in the modulation of gut microbial compositions. However, it is inappropriate to neglect the impact of host factors on shaping the gut microbiota. In this review, we highlighted the current findings of the host factors that could modulate the gut microbiota. Particularly the epithelium-associated factors, including the innate immune sensors, anti-microbial peptides, mucus barrier, secretory IgAs, epithelial microvilli, epithelial tight junctions, epithelium metabolism, oxygen barrier, and even the microRNAs are discussed in the context of the microbiota shaping. With these shaping factors, the gut epithelial cells could select the residing microbes and affect the microbial composition. This knowledge not only could provide the opportunities to better control many diseases, but may also be used for predicting the success of fecal microbiota transplantation clinically.

Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model.

The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver-expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin-evoked activity. GHSR also displays ligand-independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake-related behaviours, including binge eating. Previously, we reported that GHSR-deficient mice daily and time-limited exposed to a high-fat (HF) diet display an attenuated binge-like HF intake compared to wild-type mice. In the present study, we aimed to determine whether ligand-independent GHSR activity affects binge-like HF intake in a 4-day binge-like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge-like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K-(D-1-Nal)-FwLL-NH2 , which are both blockers of constitutive GHSR activity, reduced binge-like HF intake, whereas central administration of ghrelin or the ghrelin-evoked GHSR activity blockers [D-Lys3]-GHRP-6 and JMV2959 did not modify binge-like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge-like HF intake in mice independently of plasma levels of ghrelin and LEAP2.

Photoimmunology: how ultraviolet radiation affects the immune system.

Ultraviolet (UV) radiation is a ubiquitous component of the environment that has important effects on a wide range of cell functions. Short-wavelength UVB radiation induces sunburn and is a potent immunomodulator, yet longer-wavelength, lower-energy UVA radiation also has effects on mammalian immunity. This Review discusses current knowledge regarding the mechanisms by which UV radiation can modify innate and adaptive immune responses and how this immunomodulatory capacity can be both beneficial in the case of inflammatory and autoimmune diseases, and detrimental in the case of skin cancer and the response to several infectious agents.

Membrane Permeabilization Mechanisms.

Many antimicrobial peptides are considered to kill microbes by permeabilizing cell membranes. This chapter summarizes the driving force of peptide binding to membranes; various mechanisms of lipid bilayer permeabilization including the barrel-stave, toroidal pore, and carpet models; and modes of permeabilization of bacterial and mammalian membranes.

Antimicrobial Peptides of Multicellular Organisms: My Perspective.

Antimicrobial peptides of multicellular organisms were first characterized in the 1980s by investigators who felt that known systems of immunity could not explain what they observed: the resistance to bacterial infection of a Cecropia moth pupa lacking antibodies or lymphocytes (cecropins (Steiner 1981)), the potent microbicidal activity of neutrophils from a rabbit (defensins (Selsted et al. 1985)), and the healing of a wound on the skin of the African clawed frog without infection in a non-sterile aquarium (magainins (Zasloff 1987)). Since then AMPs have been discovered in diverse species of fungi, plants, and animals (Seshadri Sundararajan et al. 2012; Fan et al. 2016; Waghu et al. 2016; Wang et al. 2016). It is likely that we will discover that every multicellular organism expresses antimicrobial peptides as a key element of their immune system. Why are antimicrobial peptides so popular in Nature?

Intracellular Antimicrobial Peptides Targeting the Protein Synthesis Machinery.

While antimicrobial peptides (AMPs) are well-known for their disruptive effects on bacterial membranes, the mechanism of many intracellular AMPs is still being elucidated. In the recent years, it has been demonstrated that the subclass of proline-rich AMPs (PrAMPs) can pass through the bacterial membrane and kill bacteria by inhibiting protein synthesis. PrAMPs are a product of the innate immune system and are secreted in response to bacterial infection. So far PrAMPs have been identified in many arthropods, such as beetles, wasps, and flies, as well as some mammals, such as sheep, cows, and goats. PrAMPs show high potency against Gram-negative bacteria, while exhibiting low toxicity in eukaryotes, suggesting that they may represent a promising avenue for the development of future antimicrobial agents to combat the increase of multidrug-resistant bacterial pathogens. Structural and biochemical data have revealed the PrAMP binding sites on the ribosome as well as insight into their mechanisms of action. While the binding site of all so far investigated PrAMPs is situated within nascent polypeptide exit tunnel, the mechanism of action is distinct between class I and II PrAMPs. Specifically, class I PrAMPs, such as Bac7, Onc112, pyrrhocoricin, and metalnikowin, block the delivery of aa-tRNA by EF-Tu to the ribosomal A-site, whereas the class II PrAMPs, such as apidaecin 1b and Api137, act during translation termination and inhibit protein synthesis by trapping of release factors on the 70S ribosome following hydrolysis of the nascent polypeptide chain.

Selectivity of Antimicrobial Peptides: A Complex Interplay of Multiple Equilibria.

Antimicrobial peptides (AMPs) attack bacterial membranes selectively, killing microbes at concentrations that cause no toxicity to the host cells. This selectivity is not due to interaction with specific receptors but is determined by the different lipid compositions of the membranes of the two cell types and by the peculiar physicochemical properties of AMPs, particularly their cationic and amphipathic character. However, the available data, including recent studies of peptide-cell association, indicate that this picture is excessively simplistic, because selectivity is modulated by a complex interplay of several interconnected phenomena. For instance, conformational transitions and self-assembly equilibria modulate the effective peptide hydrophobicity, the electrostatic and hydrophobic contributions to the membrane-binding driving force are nonadditive, and kinetic processes can play an important role in selective bacterial killing in the presence of host cells. All these phenomena and their bearing on the final activity and toxicity of AMPs must be considered in the definition of design principles to optimize peptide selectivity.