Antimicrobial peptides

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Various structures of antimicrobial peptides Various AMPs.png
Various structures of antimicrobial peptides

Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, [1] enveloped viruses, fungi and even transformed or cancerous cells. [2] Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.

Contents

Structure

Antimicrobial peptides from animals, plants and fungi organised by their secondary structure content. Circle size indicates overall molecular weight of each peptide. Antimicrobial peptide size diversity.svg
Antimicrobial peptides from animals, plants and fungi organised by their secondary structure content. Circle size indicates overall molecular weight of each peptide.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. [3] Antimicrobial peptides are generally between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. [4] [5] [6] The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-stranded due to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. [7] Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. The peptides contain hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule. [3] This amphipathicity of the antimicrobial peptides allows them to partition into the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides, [8] [9] although membrane permeabilization is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.[ citation needed ]

TypecharacteristicAMPs
Anionic peptidesrich in glutamic and aspartic acidsMaximin H5 from amphibians, dermcidin from humans
Linear cationic α-helical peptideslack in cysteine Cecropins, andropin, moricin, ceratotoxin and melittin from insects, Magainin, dermaseptin, bombinin, brevinin-1, esculentins and buforin II from amphibians, CAP18 from rabbits, LL37 from humans
Cationic peptide enriched for specific amino acidrich in proline, arginine, phenylalanine, glycine, tryptophan abaecin and drosocin, apidaecin, diptericin, and attacin from insects, prophenin from pigs, indolicidin from cattle.
Anionic/cationic peptides forming disulfide bondscontain 1~3 disulfide bond

Activities

The modes of action by Antimicrobial peptides Modes of action.png
The modes of action by Antimicrobial peptides

The modes of action by which antimicrobial peptides kill microbes are varied, [10] and may differ for different bacterial species. [11] Some antimicrobial peptides kill both bacteria and fungi, e.g., psoriasin kills E. coli and several filamentous fungi. [12] The cytoplasmic membrane is a frequent target, but peptides may also interfere with DNA and protein synthesis, protein folding, and cell wall synthesis. [10] The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic, or hydrophobic, such as in the antimicrobial peptide Piscidin. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms. Alternately, they may penetrate into the cell to bind intracellular molecules which are crucial to cell living. [13] Intracellular binding models includes inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. In many cases, the exact mechanism of killing is not known. One emerging technique for the study of such mechanisms is dual polarisation interferometry. [14] [15] In contrast to many conventional antibiotics these peptides appear to be bactericidal [2] instead of bacteriostatic. In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), which is the lowest concentration of drug that inhibits bacterial growth. [16]

AMPs can possess multiple activities including anti-gram-positive bacterial, anti-gram-negative bacterial, anti-fungal, anti-viral, anti-parasitic, and anti cancer activities. A big AMP functional analysis indicates that among all AMP activities, amphipathicity and charge, two major properties of AMPs, best distinguish between AMPs with and without anti-gram-negative bacterial activities. [17] This implies that being AMPs with anti-gram-negative bacterial activities may prefer or even require strong amphipathicity and net positive charge.[ citation needed ]

Immunomodulation

In addition to killing bacteria directly they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to alter host gene expression, act as chemokines and/or induce chemokine production, inhibiting lipopolysaccharide induced pro-inflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells and cells of the adaptive immune response. Animal models indicate that host defense peptides are crucial for both prevention and clearance of infection. It appears as though many peptides initially isolated as and termed "antimicrobial peptides" have been shown to have more significant alternative functions in vivo (e.g. hepcidin [18] ). Dusquetide for example is an immunomodulator that acts through p62, a protein involved in toll like receptor based signalling of infection. The peptide is being examined in a Phase III clinical trial by Soligenix (SGNX) to ascertain if it can assist in repair of radiation-induced damage to oral mucosa arising during cancer radiotherapy of the head and neck. [19]

Mechanisms of action

Scanning electron microscopic images (50,000X magnification) displaying the action of an experimental antimicrobial peptide (NN2_0050) on the cell membrane of E. coli (K12 MG1655) ABOVE: Intact cell membranes in the control group. BELOW: Disrupted cell membranes and leakage of bacterial chromosome (green) in the treated group. AMP action Ecoli.jpg
Scanning electron microscopic images (50,000X magnification) displaying the action of an experimental antimicrobial peptide (NN2_0050) on the cell membrane of E. coli (K12 MG1655) ABOVE: Intact cell membranes in the control group. BELOW: Disrupted cell membranes and leakage of bacterial chromosome (green) in the treated group.

Antimicrobial peptides generally have a net positive charge, allowing them to interact with the negatively charged molecules exposed on bacteria and cancer cell surfaces, such as phospholipid phosphatidylserine, O-glycosylated mucins, sialylated gangliosides, and heparin sulfates. The mechanism of action of these peptides varies widely but can be simplified into two categories: membranolytic and non-membranolytic antimicrobial peptides. [20] The disruption of membranes by membranolytic antimicrobial peptides can be described by four models: [20]

Schematic representation of the AMPs mechanisms of action when disrupting membranes. Mecanismos disrupcion.png
Schematic representation of the AMPs mechanisms of action when disrupting membranes.

Several methods have been used to determine the mechanisms of antimicrobial peptide activity. [11] [13] In particular, solid-state NMR studies have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides. [23] [24] In more recent years, X-ray crystallography has been used to delineate in atomic detail how the family of plant defensins rupture membranes by identifying key phospholipids in the cell membranes of the pathogen. [25] [26] Human defensins have been thought to act through a similar mechanism, targeting cell membrane lipids as part of their function. In fact human beta-defensin 2 have now been shown to kill the pathogenic fungi Candida albicans through interactions with specific phospholipids. [27] From the computational point of view, Molecular Dynamics simulations can provide detailed information about the structure and dynamics of the peptide-membrane interactions, including the orientation, conformation, and insertion of the peptide in the membrane, as well as specific peptide interactions with lipids, ions and solvent. [28]

MethodsApplications
Microscopyto visualize the effects of antimicrobial peptides on microbial cells
Atomic emission spectroscopyto detect loss of intracellular potassium (an indication that bacterial membrane integrity has been compromised)
Fluorescent dyesto measure ability of antimicrobial peptides to permeabilize membrane vesicles
Ion channel formationto assess the formation and stability of an antimicrobial-peptide-induced pore
Circular dichroism and orientated circular dichroismto measure the orientation and secondary structure of an antimicrobial peptide bound to a lipid bilayer
Dual polarization interferometryto measure the different mechanisms of antimicrobial peptides
Solid-state NMR spectroscopyto measure the secondary structure, orientation and penetration of antimicrobial peptides into lipid bilayers in the biologically relevant liquid-crystalline state
Neutron and X-ray diffractionto measure the diffraction patterns of peptide-induced pores within membranes in oriented multilayers or liquids
Molecular dynamics simulationsto study the molecular behaviour and search for specific peptide-lipid interactions
Mass spectrometryto measure the proteomic response of microorganisms to antimicrobial peptides

Therapeutic research and use

Antimicrobial peptides have been used as therapeutic agents; their use is generally limited to intravenous administration or topical applications due to their short half-lives. As of January 2018 the following antimicrobial peptides were in clinical use: [29]

Activity beyond antibacterial functions

AMPs have been observed having functions other than bacterial and fungal killing. These activities include antiviral effects, but also roles in host defence such as anticancer functions and roles in neurology. [30] This has led to a movement for re-branding AMPs as "Host-defence peptides" to encompass the broad scope of activities AMPs can have. [31]

Anticancer properties

Some cecropins (e.g. cecropin A, and cecropin B) have anticancer properties and are called anticancer peptides (ACPs). [32] : 3  Hybrid ACPs based on Cecropin A have been studied for anticancer properties. [32] : 7.1  The fruit fly Defensin prevents tumour growth, suspected to bind to tumour cells owing to cell membrane modifications common to most cancer cells, such as phosphatidylserine exposure. [33]

Antibiofilm properties

Cecropin A can destroy planktonic and sessile biofilm-forming uropathogenic E. coli (UPEC) cells, either alone or when combined with the antibiotic nalidixic acid, synergistically clearing infection in vivo (in the insect host Galleria mellonella ) without off-target cytotoxicity. The multi-target mechanism of action involves outer membrane permeabilization followed by biofilm disruption triggered by the inhibition of efflux pump activity and interactions with extracellular and intracellular nucleic acids. [34]

Other research

Recently there has been some research to identify potential antimicrobial peptides from prokaryotes, [35] aquatic organisms such as fish, [36] [37] and shellfish, [38] and monotremes such as echidnas. [39] [40]

Selectivity

In the competition of bacterial cells and host cells with the antimicrobial peptides, antimicrobial peptides will preferentially interact with the bacterial cell to the mammalian cells, which enables them to kill microorganisms without being significantly toxic to mammalian cells. [41]

With regard to cancer cells, they themselves also secrete human antimicrobial peptides including defensin, and in some cases, they are reported to be more resistant than the surrounding normal cells. Therefore, we cannot conclude that selectivity is always high against cancer cells. [42] [43]

Factors

There are some factors that are closely related to the selectivity property of antimicrobial peptides, among which the cationic property contributes most. Since the surface of the bacterial membranes is more negatively charged than mammalian cells, antimicrobial peptides will show different affinities towards the bacterial membranes and mammalian cell membranes. [44]

In addition, there are also other factors that will affect the selectivity. It's well known that cholesterol is normally widely distributed in the mammalian cell membranes as a membrane stabilizing agent but absent in bacterial cell membranes (except when sequestered by H. pylori ); [45] and the presence of these cholesterols will also generally reduce the activities of the antimicrobial peptides, due either to stabilization of the lipid bilayer or to interactions between cholesterol and the peptide. So the cholesterol in mammalian cells will protect the cells from attack by the antimicrobial peptides. [46]

Besides, the transmembrane potential is well known to affect peptide-lipid interactions. [47] There's an inside-negative transmembrane potential existing from the outer leaflet to the inner leaflet of the cell membranes and this inside-negative transmembrane potential will facilitate membrane permeabilization probably by facilitating the insertion of positively charged peptides into membranes. By comparison, the transmembrane potential of bacterial cells is more negative than that of normal mammalian cells, so bacterial membrane will be prone to be attacked by the positively charged antimicrobial peptides.[ citation needed ]

Similarly, it is also believed that increasing ionic strength, [46] which in general reduces the activity of most antimicrobial peptides, contributes partially to the selectivity of the antimicrobial peptides by weakening the electrostatic interactions required for the initial interaction.

Molecular Basis of Cell Selectivity of Antimicrobial Peptides Mechanim of Selectivity of Antimicrobial Peptides.jpg
Molecular Basis of Cell Selectivity of Antimicrobial Peptides

Mechanism

The cell membranes of bacteria are rich in acidic phospholipids, such as phosphatidylglycerol and cardiolipin. [41] [48]

In contrast, the outer part of the membranes of plants and mammals is mainly composed of lipids without any net charges since most of the lipids with negatively charged headgroups are principally sequestered into the inner leaflet of the plasma membranes. [44] Thus in the case of mammalian cells, the outer surfaces of the membranes are usually made of zwitterionic phosphatidylcholine and sphingomyelin, even though a small portion of the membrane's outer surfaces contain some negatively charged gangliosides. Therefore, the hydrophobic interaction between the hydrophobic face of amphipathic antimicrobial peptides and the zwitterionic phospholipids on the cell surface of mammalian cell membranes plays a major role in the formation of peptide-cell binding. [49]

Dual polarisation interferometry has been used in vitro to study and quantify the association to headgroup, insertion into the bilayer, pore formation and eventual disruption of the membrane. [50] [51]

Control

A lot of effort has been put into controlling cell selectivity. For example, attempts have been made to modify and optimize the physicochemical parameters of the peptides to control the selectivities, including net charge, helicity, hydrophobicity per residue (H), hydrophobic moment (μ) and the angle subtended by the positively charged polar helix face (Φ). [47] Other mechanisms like the introduction of D-amino acids and fluorinated amino acids in the hydrophobic phase are believed to break the secondary structure and thus reduce hydrophobic interaction with mammalian cells. It has also been found that Pro→Nlys substitution in Pro-containing β-turn antimicrobial peptides was a promising strategy for the design of new small bacterial cell-selective antimicrobial peptides with intracellular mechanisms of action. [52] It has been suggested that direct attachment of magainin to the substrate surface decreased nonspecific cell binding and led to improved detection limit for bacterial cells such as Salmonella and E. coli . [53]

Bacterial resistance

Bacteria use various resistance strategies to avoid antimicrobial peptide killing. [13]

While these examples show that resistance can evolve naturally, there is increasing concern that using pharmaceutical copies of antimicrobial peptides can make resistance happen more often and faster. In some cases, resistance to these peptides used as a pharmaceutical to treat medical problems can lead to resistance, not only to the medical application of the peptides, but to the physiological function of those peptides. [62] [63]

The ‘Trojan Horse’ approach to solving this problem capitalizes on the innate need for iron by pathogens. “Smuggling” antimicrobials into the pathogen is accomplished by linking them to siderophores for transport. While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens. Lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the ‘Trojan horse’ approach have been reviewed. [64]

Examples

Fruit flies infected by GFP-producing bacteria. Red-eyed flies lacking antimicrobial peptide genes are susceptible to infection, while white-eyed flies have a wild-type immune response. AMP Ecc15-19-02-2019.tif
Fruit flies infected by GFP-producing bacteria. Red-eyed flies lacking antimicrobial peptide genes are susceptible to infection, while white-eyed flies have a wild-type immune response.

Antimicrobial peptides are produced by species across the tree of life, including:

Research has increased in recent years to develop artificially-engineered mimics of antimicrobial peptides such as SNAPPs, in part due to the prohibitive cost of producing naturally-derived AMPs. [69] An example of this is the facially cationic peptide C18G, which was designed from the C-terminal domain of human platelet factor IV. [70] Currently, the most widely used antimicrobial peptide is nisin; being the only FDA approved antimicrobial peptide, it is commonly used as an artificial preservative. [71]

Bioinformatics

Several bioinformatic databases exist to catalogue antimicrobial peptides. The Antimicrobial Peptide Database (APD) is the original and model database for antimicrobial peptides (https://aps.unmc.edu). Based on the APD, other databases have also been built, including ADAM (A Database of Anti-Microbial peptides), [72] BioPD (Biologically active Peptide Database), CAMP (Collection of sequences and structures of antimicrobial peptides), [73] DBAASP (Database of Antimicrobial Activity and Structure of Peptides), DRAMP(Data Repository of Antimicrobial Peptides)Welcome To Dramp Database, [74] and LAMP (Linking AMPs).

The Antimicrobial peptide databases may be divided into two categories on the basis of the source of peptides it contains, as specific databases and general databases. These databases have various tools for antimicrobial peptides analysis and prediction. For example, the APD has a widely used calculation interface. It also provides links to many other tools. CAMP contains AMP prediction, feature calculator, BLAST search, ClustalW, VAST, PRATT, Helical wheel etc. In addition, ADAM allows users to search or browse through AMP sequence-structure relationships. Antimicrobial peptides often encompass a wide range of categories such as antifungal, antibacterial, and antituberculosis peptides.

dbAMP: [75] Provides an online platform for exploring antimicrobial peptides with functional activities and physicochemical properties on transcriptome and proteome data. dbAMP is an online resource that addresses various topics such as annotations of antimicrobial peptides (AMPs) including sequence information, antimicrobial activities, post-translational modifications (PTMs), structural visualization, antimicrobial potency, target species with minimum inhibitory concentration (MIC), physicochemical properties, or AMP–protein interactions.[ citation needed ]

Tools such as PeptideRanker, [76] PeptideLocator, [77] and AntiMPmod [78] [79] allow for the prediction of antimicrobial peptides while others have been developed to predict antifungal and anti-Tuberculosis activities. [80] [81]

See also

Related Research Articles

<span class="mw-page-title-main">Membrane protein</span> Proteins that are part of, or interact with, biological membranes

Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane and can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane. Peripheral membrane proteins are transiently associated with the cell membrane.

<span class="mw-page-title-main">Transmembrane protein</span> Protein spanning across a biological membrane

A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

<span class="mw-page-title-main">Polymyxin</span> Group of antibiotics

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Defensin</span> Group of antimicrobial peptides

Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.

<span class="mw-page-title-main">Amphiphile</span> Hydrophilic and lipophilic chemical compound

An amphiphile, or amphipath, is a chemical compound possessing both hydrophilic and lipophilic (fat-loving) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic compounds include surfactants. The phospholipid amphiphiles are the major structural component of cell membranes.

<span class="mw-page-title-main">Paneth cell</span> Anti-microbial epithelial cell of the small intestine

Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands and the large eosinophilic refractile granules that occupy most of their cytoplasm.

<span class="mw-page-title-main">Surfactin</span> Chemical compound

Surfactin is a cyclic lipopeptide, commonly used as an antibiotic for its capacity as a surfactant. It is an amphiphile capable of withstanding hydrophilic and hydrophobic environments. The Gram-positive bacterial species Bacillus subtilis produces surfactin for its antibiotic effects against competitors. Surfactin showcases antibacterial, antiviral, antifungal, and hemolytic effects.

Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the CAMP gene. The active form is LL-37. In humans, CAMP encodes the peptide precursor CAP-18, which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.

<span class="mw-page-title-main">Alpha defensin</span>

Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. They are also known as cryptdins and are produced within the small bowel. Cryptdin is a portmanteau of crypt and defensin.

<span class="mw-page-title-main">Plant defensin</span> Host-defense peptide family in plants

Plant defensins are a family of primitive, highly stable, cysteine-rich defensins found in plants that function to defend them against pathogens and parasites. Defensins are integral components of the innate immune system and belong to the ancient superfamily of antimicrobial peptides (AMPs). AMPs are also known as host defense peptides (HDPs), and they are thought to have diverged about 1.4 billion years ago before the evolution of prokaryotes and eukaryotes. They are ubiquitous in almost all plant species, functionally diverse, and their primary structure varies significantly from one species to the next, except for a few cysteine residues, which stabilize the protein structure through disulfide bond formation. Plant defensins usually have a net positive charge due to the abundance of cationic amino acids and are generally divided into two classes. Those in the class II category contain a C-terminal pro-peptide domain of approximately 33 amino acids and are targeted to the vacuole, while the class I defensins lack this domain and mature in the cell wall. Unlike their class I counterparts, class II plant defensins are relatively smaller, and their acidic C-terminal prodomain is hypothesized to contribute to their vacuolar targeting. The first plant defensins were discovered in barley and wheat in 1990 and were initially designated as γ-thionins. In 1995, the name was changed to 'plant defensin' when it was identified that they are evolutionarily unrelated to other thionins and were more similar to defensins from insects and mammals.

A lipopeptide is a molecule consisting of a lipid connected to a peptide. They are able to self-assemble into different structures. Many bacteria produce these molecules as a part of their metabolism, especially those of the genus Bacillus, Pseudomonas and Streptomyces. Certain lipopeptides are used as antibiotics. Due to the structural and molecular properties such as the fatty acid chain, it poses the effect of weakening the cell function or destroying the cell. Other lipopeptides are toll-like receptor agonists. Certain lipopeptides can have strong antifungal and hemolytic activities. It has been demonstrated that their activity is generally linked to interactions with the plasma membrane, and sterol components of the plasma membrane could play a major role in this interaction. It is a general trend that adding a lipid group of a certain length to a lipopeptide will increase its bactericidal activity. Lipopeptides with a higher amount of carbon atoms, for example 14 or 16, in its lipid tail will typically have antibacterial activity as well as anti-fungal activity. Therefore, an increase in the alkyl chain can make lipopeptides soluble in water. As well, it opens the cell membrane of the bacteria, so antimicrobial activity can take place.

Protein–lipid interaction is the influence of membrane proteins on the lipid physical state or vice versa.

<span class="mw-page-title-main">Cecropin</span>

Cecropins are antimicrobial peptides. They were first isolated from the hemolymph of Hyalophora cecropia, whence the term cecropin was derived. Cecropins lyse bacterial cell membranes; they also inhibit proline uptake and cause leaky membranes.

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.

Polymers with the ability to kill or inhibit the growth of microorganisms such as bacteria, fungi, or viruses are classified as antimicrobial agents. This class of polymers consists of natural polymers with inherent antimicrobial activity and polymers modified to exhibit antimicrobial activity. Polymers are generally nonvolatile, chemically stable, and can be chemically and physically modified to display desired characteristics and antimicrobial activity. Antimicrobial polymers are a prime candidate for use in the food industry to prevent bacterial contamination and in water sanitation to inhibit the growth of microorganisms in drinking water.

<span class="mw-page-title-main">Cell membrane</span> Biological membrane that separates the interior of a cell from its outside environment

The cell membrane is a biological membrane that separates and protects the interior of a cell from the outside environment. The cell membrane consists of a lipid bilayer, made up of two layers of phospholipids with cholesterols interspersed between them, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as membrane transporters, and peripheral proteins that loosely attach to the outer (peripheral) side of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment. Glycolipids embedded in the outer lipid layer serve a similar purpose. The cell membrane controls the movement of substances in and out of a cell, being selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate layer called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.

Virtual colony count (VCC) is a kinetic, 96-well microbiological assay originally developed to measure the activity of defensins. It has since been applied to other antimicrobial peptides including LL-37. It utilizes a method of enumerating bacteria called quantitative growth kinetics, which compares the time taken for a bacterial batch culture to reach a threshold optical density with that of a series of calibration curves. The name VCC has also been used to describe the application of quantitative growth kinetics to enumerate bacteria in cell culture infection models. Antimicrobial susceptibility testing (AST) can be done on 96-well plates by diluting the antimicrobial agent at varying concentrations in broth inoculated with bacteria and measuring the minimum inhibitory concentration that results in no growth. However, these methods cannot be used to study some membrane-active antimicrobial peptides, which are inhibited by the broth itself. The virtual colony count procedure takes advantage of this fact by first exposing bacterial cells to the active antimicrobial agent in a low-salt buffer for two hours, then simultaneously inhibiting antimicrobial activity and inducing exponential growth by adding broth. The growth kinetics of surviving cells can then be monitored using a temperature-controlled plate reader. The time taken for each growth curve to reach a threshold change in optical density is then converted into virtual survival values, which serve as a measure of antimicrobial activity.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They include ghrelin, a peptide hormone associated with feeding. Many proteolipids are composed of proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

References

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