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Introductory Chapter: Antimicrobial Peptides – Prodigious Therapeutic Strategies

Written By

Jorge Masso-Silva, Anna Savitskaya and Shymaa Enany

Published: 06 July 2022

DOI: 10.5772/intechopen.101516

From the Edited Volume

Insights on Antimicrobial Peptides

Edited by Shymaa Enany, Jorge Masso-Silva and Anna Savitskaya

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1. Introduction

Antimicrobial peptides (AMPs) exist in all living things, from unicellular to more complex multicellular organisms [1]. They are at the frontline of defense against microbial pathogens [1, 2]. In less complex organisms, AMPs represent a major part of their arsenal against detrimental organisms, and on the other hand, more evolved organisms have a wider repertoire of biological weapons against these detrimental organisms [3, 4]. AMPs are typically amphipatic small peptides usually under 50 amino acids with a net positive charge at physiological pH [5].

Although AMPS were described for the first time in the 1960s, it was until 1980s were the AMP called cecropin was identified and characterized from a moth [6]. Since then, many AMPs have been identified in all different taxa from microorganisms, plants, invertebrates, and vertebrates [3]. In vertebrates, AMPs have been widely characterized in all different phylogenetic classes, from fish to mammals [3, 7]. Currently, over 2600 AMPs have been identified, and most of them in eukaryotes [8].

In vertebrates, AMPs can be expressed in different compartments, from the skin to specific cells within internal organs and blood. Thus, their action can be found throughout the whole body, and this is where the relevance of AMPs relies on for the protection of the host.

In addition, in other taxa, gene duplication has been an important factor for the evolution of AMPs. In plants, for example, gene duplication has led to the creation of large families of AMPs. For example, in plants such as Arabidopsis and Medicago up to 300 different sequences of defensin and defensin-like have been found [4, 9].

Although for many years it was thought that the main role of AMPs was the killing of pathogens to resolve infections, now it is known that the variety of functions of AMPs ranges from direct antimicrobial activity to a wide range of immunomodulatory mechanisms, hence their importance in host defenses. In infections, depending on the phase of infection, their immunomodulatory activity can be either pro- or anti-inflammatory [5]. Initially, the scientific community focused their research on the potential of AMPs as therapeutics due to their antibiotic properties, although now it is well established that AMPs have more roles beyond that and are playing a key role in immunity [5].


2. Classes of antimicrobial peptides

Despite that most AMPs are amphipathic, they can differ significantly in sequence and structure. To simplify their classification due to their wide diversity, AMPs have been classified based on (1) source, (2) activity, (3) structural characteristics, and (4) amino acid-rich species [10]. Based on source, they can be divided into mammals, amphibians, microorganisms, and insects. In mammals and vertebrates in general, the two main classes of AMPs are defensins and cathelicidins, which are produced as prepropepides that required site-specific cleavage to reach their mature and active form [1, 11]. Based on their activity, they can be divided into 18 categories according to the ADP3 database, which can be summarized as antibacterial, antiviral, antifungal, antiparasitic, antihuman immunodeficiency virus (HIV), and antitumor peptides [10]. Based on structure, they are divided into four structures due to their tridimensional conformation: α-helical linear peptides, peptides with β-sheet forming disulfide bridges, with both α-helix and β-sheet peptides, and peptides with extended flexible loop structures [3, 4, 10]. In addition, cyclic AMPs with more complex topologies are also reported [10]. Finally, based on amino acid rich context, they are divided into proline-rich, tryptophan- and arginine-rich, histidine-rich, and glycine-rich antimicrobial peptides [10].


3. Mechanism of action

In terms of their mechanism of action, bacteria membranes have been a key model to assess direct antimicrobial activity, which are initiated through electrostatic interaction from the cationic nature of AMPs and the negative charge of bacterial membranes due to the anionic lipids (lipopolysaccharides in Gram-negative batceria and teichoic acid in Gram-positive bacteria) [5]. This results in poor interaction with membranes of cells from plants, invertebrates, and vertebrates. There are four different models in which AMPs can interact with bacterial cells, leading to leakage of the cell content and further cell death. These models are 1) aggregate, 2) toroidal pore, 3) barrel stave, and 4) carpet [3]. Amphipatic AMPs possess amino acids with hydrophilic and hydrophobic side chains at opposite sides, which allow them to interact with membranes of bacteria that are negatively charged [5].

In the case of viruses, several mechanisms of action have been identified, such as the destabilization of viral envelope on contact (damaging virions and thus diminishing their infectivity), decreasing viral replication and/or binding of viral capsid (preventing entry of the viral genome), aggregation of viral particles, and immunomodulation [3, 5]. For antifungal purposes, it has been reported that AMPs effects range from the membrane effects to impairment in mitochondrial function [5, 12, 13]. It is important to consider that fungi can form biofilms, which are highly resistant to antifungals, which challenge even more the identification and development of biofilm-forming fungi [14].

Besides the direct microbicidal activity, immunomodulatory function of AMPs has been of a key focus from more recent years. The studies have define a diverse range of immunomodulatory function that is highly complex and seems to be dependent on the environmental stimuli, cell and tissue type, interaction with different cellular receptors, and the concentration of the peptides [3, 5, 15]. AMPs can interact with both membrane-associated and intracellular receptors, and they can cause alterations of several signaling pathways and engagement with different transcription factors [2, 15].

3.1 Therapeutic use

Since the discovery of AMPs, a significant part of their research has been focused on their potential therapeutic use. Currently, with the raise of antibiotic resistance, there is an increasing challenge for human health. The development of more efficient antibiotics has decreased as compared with previous years, and along with the abuse of the use of these antibiotics, we have created the conditions to originate bacteria super resistant of widely used antibiotics, which has generated incredible economical and health burden [5, 16, 17]. This phenomenon has also occurred with fungi, whose incidence still affects millions of individuals every year [18]. Thus, there has been an urgent need for the generation of new antibiotics with low potential for the generation of resistance.

As mentioned before, due to the mechanism of action of AMPs that rely mostly in electrostatic interactions and not in specific targets, it was thought that it is unlikely that microbes can become resistant to AMPs. Thus, this feature of AMPs have attracted investigators and industry to study them with the goal to be use as therapeutics against pathogenic bacteria mostly, although some studies have address this approach against fungi [19], viruses [20], and parasites [21]. However, there is evidence of resistance to direct killing by AMP and related synthetic analogs by multiple mechanisms from bacteria [22, 23, 24]. Although in consequence of the generation of resistance to AMPs, there is a cost in fitness for infectivity leading to impaired survival and pathogencity in vivo [25]. Thus, there is a current area of research in AMPs focusing more in harnessing the immunomodulatory actions of AMPs in order to enhance host immune responses rather that direct killing of the pathogen [5]. Moreover, their synergistic potential as adjuvants with other antimicrobial compounds is another area of interest [26].

The use of natural AMPs has shown poor viability due to the relatively high concentrations necessary at which these AMPs have to be affective, which often leads to cytotoxicity [5]. Thus, synthetic peptides derived from natural AMPs have been generated. Due to the limitations of natural AMPs, there has been an increasing interest in developing non-peptide analogs that mimic the properties and functions of natural AMPs in order to overcome these limitations [27]. An example of non-peptides AMP mimics are peptide analogs, which are usually developed on small abiotic scaffolds [28]. Early approaches focused on optimizing their microbicidal properties, although often this led to increased levels of cytotoxicity as their natural counterparts. Thus, more recent approaches have focused on mimicking the immunomodulatory properties of AMPs along with their potential microbicidal activity [5, 29].

Exogenous administration of many AMPs has been found to be effective in various animal models for bacterial, viral, and fungal infections. However, this efficacy can be due in part to immunomodulatory effects and not only direct antimicrobial activity [5]. Studies have shown the potential immunodulatory role of AMPs to treat non-infectious inflammatory diseases such as in arthritis [30], asthma [31], colitis [32], and even cancer [33]. Alternatively, instead of exogenous administration, others had opted for enhancing the expression of endogenous AMPs for chronic inflammatory and infectious disease [5].

Most AMPs and AMPs analogs have reached clinical trial that has been formulated for topical application or as inhalants [34]. However, there are also clinical trials for oral and intravenous AMP or AMP analogs [5]. Some of these clinical trials have reached phase III, despite their development had been terminated [5, 34]. This step missing for full approval to be released in the market has to do with regulations that require new antimicrobial to perform better in terms of efficacy to control infections than existing antibiotics, even if the new compound does not generate antimicrobial resistance [5].

Still, the challenges to bring peptide-based AMP compounds to the market involved formulation, delivery, and costs. Biologically, factors to be considered include peptide stability and bioavailability since pH or proteases present in the body can degrade such peptides. Moreover, other factors present in the host-like physiological salt concentrations, mucus, DNA, and microbial saccharides can impair peptide activity [5].

This book will be touching a wide variety of aspects in the field of AMPs, from their basic biological roles to their potential use in medicine. The research on AMPs is a growing field that keeps expanding year after year. We expect the reader to use this book as a nutritive source of information to better understand about the field of AMPs and also to encouraging going beyond of what has been embodied here.


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Written By

Jorge Masso-Silva, Anna Savitskaya and Shymaa Enany

Published: 06 July 2022