Current Pharmaceutical Design - Volume 24, Issue 10, 2018

Antimicrobial peptides (AMPs) are phylogenetically ancient substances released by living organisms for self protection against a broad variety of microbes. Moreover, AMPs are endowed with immune modulatory activities, linking innate and adaptive immunity together. Lantibiotics are AMPs of bacterial origin currently investigated for the generation of a new class of anti-infective compounds, owing to the phenomenon of antibiotic resistance against a broad variety of bacteria. Also, plants and marine AMPs are screened as novel drugs against human pathogens. Human AMPs encompass defensins and cathelicidins produced by various cell types mostly at mucosal sites. Besides their antimicrobial activity, both AMPs have been shown to trigger either inflammatory or anti-inflammatory pathways. Food-derived AMPs are mostly represented by lactoferrin and lysozyme both present in secretions, e.g., milk, and appear to be very exploitable for the generation of functional foods. Finally, the role of natural products ingested with food or administered as supplements on induction and production of AMPs will be discussed.

Cationic antimicrobial peptides (CAMPs), also known as host defence peptides (HDPs), are essential evolutionarily conserved components of innate immunity, constitutively or inducibly expressed in response to invasion by pathogens. In addition to a direct antimicrobial action, they are able to synergistically operate with other defence molecules to combat infection by neutralization of endotoxins, chemokine-like activities, induction of angiogenesis and wound repair. The importance of CAMPs has been highlighted in animal models and supported by observations in patient studies. CAMPs are attractive alternative candidates to antibiotic treatment, because they offer several advantages over the currently used drugs, moreover, knowledge on these peptides, especially regarding the intertwinement between their structure, function and mechanism of action, could be applied in the rational design of antimicrobial/anti-inflammatory/wound healing enhancing drugs. CAMPs combat pathogens by targeting bacterial membranes and essential membrane-related functions, and, in some cases, also target intracellular components. Despite differences in their size and sequence, many of them share a net positive charge and fold into amphipathic structures after contact with bacterial surfaces or endotoxins like lipopolysaccharides and lipoteichoic acid. Due to their peculiar mechanism, acquisition of resistance towards these peptides would be difficult for the bacteria. Very interestingly it has been demonstrated that several proteins, including proteins apparently not involved in immunity, can behave as sources of CAMPs hidden in their primary structures and released by the action of host and/or bacterial proteases. The existence of these “cryptic CAMPs” suggests that the panel of antimicrobial peptides present in higher eukaryotes and the variety of functions they perform could be much wider and more complex than previously suspected. This review focuses on source, structure and mechanism of action of cryptic CAMPs, with special attention to their immunomodulatory functions.

Lactoferrin (Lf) is a conserved cationic non-heme glycoprotein that is part of the innate immune defense system of mammals. Lf is present in colostrum, milk and mucosal sites, and it is also produced by polymorphonuclear neutrophils and secreted at infection sites. Lf and Lf N-terminus peptide-derivatives named lactoferricins (Lfcins) are molecules with microbiostatic and microbicidal action in a wide array of pathogens. In addition, they display regulatory properties on components of nonspecific immunity, including toll-like receptors, proand anti-inflammatory cytokines, and reactive oxygen species. Mechanisms explaining the ability of Lf and Lfcins to display both up- and down-modulatory properties on cells are not fully understood but result, in part, from their interactions with membrane receptors that elicit biochemical signal pathways, whereas other receptors enable the nuclear translocation of these molecules for the modulation of target genes. The dual role of Lf and Lfcins as antimicrobials and immunomodulators is of biotechnological and pharmaceutical interest. Native Lf and its peptide-derivatives from human and bovine sources, the recombinant versions of the human protein, and their synthetic peptides have potential application as adjunctive agents in therapies to combat infections caused by multi-resistant bacteria and those caused by fungi, protozoa and viruses, as well as in the prevention and reduction of several types of cancer and response to LPS-shock, among other effects. In this review, we summarize the immunomodulatory properties of the unique multifunctional protein Lf and its N-terminus peptides.

Cathelicidins form one of the major families of antimicrobial peptides and have been identified in many vertebrates, including humans. LL-37, the only human member of the cathelicidin family, is detected in most sites of the human body that is normally exposed to microbes, including the epithelial lining of the skin, gastrointestinal tract, genitourinary tract and lungs. This peptide is also expressed by a variety of epithelial cells and immune cells, such as neutrophils, monocytes and mast cells. LL-37 has emerged as a key component of innate immunity due to its direct antimicrobial activity against a broad spectrum of invading pathogens. It also exhibits diverse immunomodulatory functions by activating both pro- and anti-inflammatory mediators; inducing cell migration, proliferation and differentiation; and regulating apoptosis of epithelial cells and neutrophils. Given that the phenotypic and functional properties of immune compartments are different and significantly impacted by the anatomical sites, tissue-specific factors of host origin and microbial communities play important roles in the regulation of LL-37. This review summarizes the expression and biological functions of LL-37 and discusses its significant roles in the innate immune system based on its anatomical distribution.

The epidermis functions as a first-line defense barrier that protects the body from the external environment. As a chemical hindrance, the epidermis possesses acidic pH, highly organized lipids and various host defense peptides, also known as antimicrobial peptides. Human β-defensins (hBDs), one of the most important host defense peptide families found in our skin, are well-known for their broad-spectrum microbicidal activities. However, there is a growing body of evidence indicating that hBDs also orchestrate several immunomodulatory functions and are the cornerstone that bridges the innate and adaptive immune responses during skin inflammation and infection. Moreover, recent work identified the potential role of hBDs in the regulation and maintenance of the skin barrier function. In this review, we describe the current knowledge concerning the role of hBDs in skin barriers and discuss the potential clinical implications of these peptides in cutaneous biology. Understanding the roles of hBDs in the regulation and maintenance of skin barriers may aid in the development of novel therapeutic strategies for skin conditions where the skin barrier is impaired, such as atopic dermatitis and psoriasis.

In recent years, the therapeutic potential of antimicrobial peptides (AMPs) as immunomodulators has become generally accepted. Nevertheless, only very few AMP-based compounds have progressed into clinical trials. This paradox may be explained by the fact, that some of the intrinsic properties of natural peptides, such as proteolytic and oxidative instability, render them inconvenient as therapeutics. Therefore, substantial research efforts have been dedicated to mimic the physico-chemical properties as well as biological activities of AMPs by designing and identifying more stable peptidomimetics displaying analogous immunomodulatory activity profiles. Neutrophils play key roles in host defense as major effector cells in clearance of pathogens by phagocytosis and by regulating other processes of innate immunity as well as by promoting resolution of inflammation. Several aspects of these effects are correlated to their expression of formyl peptide receptors (FPRs) that have been shown to be targets of both natural and synthetic antimicrobial peptides. In the present review recent findings highlighting the role of FPRs in mediating immunomodulatory activities of natural and synthetic AMPs as well as of stabilized peptidomimetics are discussed, and prospects for future development of immunomodulatory therapeutics are presented.

Since the initial description of granular-rich small-intestinal crypt-based epithelial cells in 1872, today referred to as Paneth cells, a plethora of recent studies underlined their function in intestinal homeostasis. Paneth cells are evolutionary conserved highly secretory cells that produce antimicrobials to control gut microbial communities. Moreover, Paneth cells emerged as stem cell regulators that translate environmental cues into intestinal epithelial responses. Paneth cell disturbances may instigate intestinal inflammation and provide susceptibility to infection. Altered Paneth cell functions have been associated with a variety of inflammatory disease models and were linked to human intestinal disease processes including inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. This review summarizes our current understanding of Paneth cells and their antimicrobials in health and disease.

The nature and structural composition of antimicrobial peptides are derived from their innate immune response and they are active against various bacteria, fungi and other microorganisms. The aim of this paper was to pool up the literature on the features of human oral defensins antimicrobial peptides. The defensins showed antimicrobial activity against Gram-positive and Gram-negative bacteria and various fungi and viruses. As with their other properties like antiviral, antifungal and antibacterial, human defensins peptides are thought to have a unique amino acid-based structure with Disulphide Bridge which makes them synthesize chemically or naturally with the help of these bacteria. The data contributing in this study was gathered from the research papers published in English language in the last twenty-five years. This literature mainly elaborates the general and analytical characteristics of antimicrobial peptides in the human oral cavity; focusing on the types, biochemistry, and mechanism of action of defensins with its clinical importance.

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

Antimicrobial Peptides (AMPs) are produced by a variety of human immune and non immune cells in health and disease. In virtue of their antimicrobial activity, AMPs have been exploited in human disease and here this aspect will extensively be described. AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activity without inducing microbial resistance. Therefore, their use in the course of antibiotic-resistant infections is justified. AMP activity in early life, in the airways, in the oral and gastro-enteric system, in the skin and in the female reproductive tract, respectively, will be elucidated. In addition, the use of AMPs in sepsis will be discussed due to the frequency of this pathological condition characterized by multiple organ dysfunctions. Finally, the evidence that AMPs represent valid substitutes of antibiotics will be provided and a series of novel substances able to reinforce the innate immune response in different clinical settings will be discussed.