Antimicrobial Peptides from Photosynthetic Marine Organisms: History
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José María García-Beltrán
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Marta Arizcun
,
Elena Chaves-Pozo

Antimicrobial peptides (AMPs) are small peptides that may be promising candidates to replace antibiotics because they are the first line of defense in animals against a wide variety of pathogens and have no negative effects; they also show additional activities such as antioxidant or immunoregulatory functions, which makes them powerful alternatives for use in aquaculture. AMPs are highly available in natural sources and have already been used in the livestock farming and food industries.

  • antimicrobial peptides
  • algal peptides
  • antioxidant

1. Introduction

Antimicrobial peptides (AMPs) are small peptides that are generally formed by fewer than 50 amino acids [1][2], weigh less than 10 kDa [3][4], and have a wide range of antimicrobial activities [2][5]. AMPs are phylogenetically ancient and highly conserved molecules that have a crucial role in the immune system of living organisms as the first line of defense against a broad variety of pathogens such as Gram− and Gram+ bacteria, viruses, fungi, and parasites [1][2][3][4][5][6][7]. Their characteristics and structure allow them to have a wide variety of mechanisms of action to prevent the development of antimicrobial resistance [1][2][4][6][8]. In contrast to antibiotics, AMPs can target the entire surface of cell membranes [4], are less likely to be targeted by proteases of microorganisms as they have unique protease-binding epitopes, and are active at quite low minimum inhibitory concentrations (MICs) [2]. That is why AMPs have already been used in the livestock farming and food industries, as they can improve animal immunity and increase production performance, and they can also be used as food preservatives in the production and storage of dairy products, meat products, and canned food as they inhibit the growth of many microorganisms [6]. In fact, as food preservatives, AMPs are well digested and hydrolyzed, have no toxic side effects, have good solubility, are active under acidic conditions, and are safer than most preservatives [6]. So, although certain aspects have to be studied before AMPs can be used in aquaculture, they are a promising option to achieve the Blue Transformation initiative proposed by the Food and Agriculture Organization (FAO) that aims for economically and environmentally sustainable aquaculture and better food security [9].

2. Classification of Antimicrobial Peptides

Generally, AMPs are small, positively charged, amphipathic molecules that have both hydrophilic and hydrophobic surfaces [3]. AMPs are classified based on multiple features due to their huge diversity (for review, see [10] and the Antimicrobial Peptide Database (APD), https://aps.unmc.edu/ accessed on 17 March 2023). In general, the main classifications are based on source, activity, or structural characteristics [10]. AMPs are produced by bacteria, fungi, plants, and animals, including invertebrates, amphibians, fish, birds, and mammals [6][10]. The APD uses 25 biological activities to classify around 3569 AMPs from all life kingdoms [11]. Zhang et al. [6] classified them according to their structural features, based on length, hydrophobic amino acid content, charge, and secondary structure. In terms of length, approximately 90% of AMPs present fewer than 50 amino acids, and most functional peptides have fewer than 30 amino acids. Regarding hydrophobicity, most AMPs have a hydrophobic amino acid content of 50%. Hydrophobicity is crucial in their antimicrobial activity, as it allows them to interact with the cell membranes of pathogens. As to their charge, almost 90% of AMPs are cationic, with a net positive charge of +1 to +13 due to arginine and lysine residues, enabling them to bind to negatively charged bacterial cell membranes [6]. Finally, according to their secondary structure, AMPs are classified as linear or cyclic, containing α-helical, hairpin-like β-sheet, or mixed α-helical/β-sheet structures stabilized by two, three, or four disulfide bonds between cysteine residues. Moreover, AMPs present an abundance of amino acids such as proline, tryptophan, histidine, and glycine [1][3][6][12].

3. Mode of Action of Antimicrobial Peptides

Understanding the main differences between prokaryotic and eukaryotic cell membrane structures, including the absence of cholesterol and a greater presence of anionic lipids in prokaryotic membranes [1], is key to understanding the preferential activity of AMPs against bacteria and their low toxicity against eukaryotic cells [1][3]. Regarding the mode of action, great diversity and specificity among particular AMP–bacteria couplings have been described [1]. First of all, there is electrostatic binding between the positively charged AMPs and the negatively charged lipids present in the membranes of microorganisms. Secondly, the secondary and amphiphilic structure of AMPs helps them to insert into or cross through the cell membrane. Thus, the α-helix domains of AMPs are related to their linkage with the phospholipid bilayer, while the β-folded domains are important for stability and crossing the cell membrane [6]. Afterwards, the antimicrobial activity of AMPs may or may not involve membrane damage [1][3][4][6]. Regarding their activity in membrane damage, different models of action have been postulated [1][3][4][6]. In the aggregation model, AMPs create irreversible membrane pores or ion channels, but in the carpet and agglutination models they can also induce membrane disruption and cytoplasm efflux, which in turn results in osmotic lysis of the cell [1][3][4][6]. On the other hand, AMPs that are able to cross the bacterial phospholipid bilayer subsequently inhibit bacterial growth and metabolism by disrupting cellular processes when binding intracellular components [1][2][3][4][6] or block the energy production and transfer pathway, triggering cell death [4].
In contrast to the bactericidal activity of AMPs, little knowledge is available about the molecular mechanism of their antiviral activity, and much less is available about their parasitic activity [13]. AMPs may have stage-specific action on different viruses at extracellular or intracellular stages of the viral cycle [14]. Regarding their action at extracellular stages, some AMPs can block or reduce the infectivity of viruses [15] directly, by disrupting the viral envelope [16][17][18][19], causing disintegration of the viral capsid or agglutination of viral particles [16][17][18][19][20], or indirectly, by competing for protein link sites in host cell membranes [16][21]. In any case, they prevent the penetration of viruses into host cells and subsequent replication [18][19]. The AMPs that act intracellularly can also selectively inhibit viral protein synthesis or the release of viral particles by interfering with the intracellular transport of capsid proteins to the cell surface and preventing the insertion of virions into the cell membrane [22].
Regarding the antiparasitic mode of action of AMPs, it seems to be based on their capability to distinguish the lipid composition of plasma membranes [23]. The plasma membranes of lower eukaryotes (parasites), compared to vertebrates (hosts), have anionic phospholipids at their outer leaflet, as well as different levels of sterols and plasma membrane potential, which allow mechanisms of action based on disrupting membranes, as previously described for AMPs (for review, see [23]).

4. Antimicrobial Peptides from Marine versus Terrestrial Sources

In addition to the abiotic condition of the oceans, including pressure, temperature range, light penetration, oxygen and salt concentration, light radiation exposure, and a wide range of microbes (bacteria and viruses), marine organisms naturally produce chemically diverse bioactive compounds that are considered essential for the discovery and development of new pharmaceutical drugs [1][3][4][24][25][26][27][28]. Marine AMPs have a different structure than terrestrial AMPs because they have had to adapt to higher concentrations of free ions in the marine environment as a result of the high salt concentration [1]. Therefore, marine AMPs present various post-translational modifications, which are required for their stability and at the same time allow them to interact with target surfaces [1]. Among these post-translational modifications are bromination, chlorination, C-terminal amidation, a high content of certain amino acids (such as phenylalanine and arginine), the modification of single amino acids (such as 3-methylisoleucine), and the presence of D-amino acids [1]. Due to these modifications, marine AMPs have a different isoelectric point (pI), secondary structure, hydrophobicity, and amphipathicity than AMPs from terrestrial sources [1]. All of these features have attracted the interest of the pharmaceutical sector, and some marine peptides have already been approved by the United States Food and Drug Administration (FDA) as pharmaceuticals for human medicine [8][12]. However, the huge biodiversity in the oceans leads to the supposition that the majority of marine AMPs are still unknown.

5. Antimicrobial Peptides from Photosynthetic Organisms

Photosynthetic marine organisms include algae (micro- and macroalgae) and bacteria (cyanobacteria). Cyanobacteria, or blue-green algae, are a diverse group of prokaryotes that can produce huge numbers of AMPs through either ribosomal or non-ribosomal biosynthesis [8][29][30]. Non-ribosomal peptide (NRP) synthesis is carried out by NRP synthetases (NRPSs), which are organized in an array of modules constituting a separate functional entity that adds new building blocks to the polypeptide chain. In addition, each module can add modifications to the monomer [30][31][32][33]. Together with monomer modifications carried out by the additional domains from some NRPS modules, the incorporation of polyketide moieties by polyketide synthases (PKSs) increases the number of modifications, which in turn increases the variability of peptides [8][24][30][31][32][33][34].
These post-translational modifications are well documented in reviews by Rivas and Rojas [30] and Ribeiro et al. [31]. According to these reviews, cyclization between the amino and carboxylic terminals through an amide bond results in the formation of head-to-tail, chemically stable lactone, ether, thioether, and disulfide bonds, among others. This cyclization confers resistance to exopeptidase degradation, extends the half-life, and improves passive diffusion of the peptide across biological membranes. Moreover, cyclic AMPs can incorporate polyketide moieties or heterocycles. Peptides can also incorporate carbohydrates and lipids. Among the lipids, saturated and unsaturated fatty acids (lipo- and depsi-peptides) [1], cholesterol, phospholipids, and glucolipids are incorporated through an amide, thioether, or ester bond [21][31]. This lipidation contributes to the acquisition of the biologically active conformation of the peptide, increases its overall hydrophobicity, and provides the capability of anchoring to the target cell membrane and subsequent disruption of the phospholipid bilayer. The hydrophobicity of the peptides is also increased by N-methylation, which also confers rigidity to cyclic AMPs [30]. The presence on AMPs of D-amino acids instead of L-amino acids (stereoisomerism) makes peptides resistant to proteolysis and helps in the acquisition of an optimal conformation for their biological function. Finally, heterocyclation, which is the cyclation of serine, threonine, or cysteine residues, gives rise to oxazole (Ozl), methyl-oxazole (mOzl), thiazole (Tzl), methyloxazoline (mOzn), and thiazoline (Tzn) rings and provides greater rigidity to the peptide scaffold, which might be important in redox reactions [30].
Although the identification and characterization of the biological activity of discrete peptides is a quite novel field of study, a huge number of cyanobacterial AMPs with many interesting biological activities and post-translational modifications have been discovered (for review, see [29][30][31][32][33][34][35][36]). Due to the great variability of cyanobacterial AMPs, researchers only included AMPs that display biological activities that could be important in aquaculture, such as antimicrobial, antioxidant, and immunoregulatory activities. Peptides with antitumor, anticoagulant, antihypertensive, antidiabetic, antiobesity, or antifatigue activities, among others, were not considered. 
Contrary to cyanobacteria, which present ribosomal and non-ribosomal biosynthesis, eukaryotic algae only have ribosomal peptide (RP) biosynthesis capability. Peptides from micro- and macroalgae are encoded by genes and synthetized by the ribosomal machinery. Therefore, they present the 20 proteinogenic amino acids with few post-translational modifications [8][30][34]. As in the case of cyanobacterial AMPs, only those that have activities relevant to aquaculture were considered. 

This entry is adapted from the peer-reviewed paper 10.3390/md21050290

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