Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

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Antimicrobial peptides of multicellular organisms

Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. 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. Although these models are helpful for defining mechanisms of antimicrobial peptide activity, their relevance to how peptides damage and kill microorganisms still need to be clarified. Recently, there has been speculation that transmembrane pore formation is not the only mechanism of microbial killing. In fact several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity. In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented.

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?

The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.

Defensins: antimicrobial peptides of innate immunity.

The concept of innate immunity refers to the first-line host defense that serves to limit infection in the early hours after exposure to microorganisms. Recent data have highlighted similarities between pathogen recognition, signaling pathways, and effector mechanisms of innate immunity in Drosophila and mammals, pointing to a common ancestry of these defenses. In addition to its role in the early phase of defense, innate immunity in mammals appears to play a key role in stimulating the subsequent, clonal response of adaptive immunity.

/pdf/phylogenetic-perspectives-in-innate-immunity-1u8kp8a668.pdf

Phylogenetic Perspectives in Innate Immunity

Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents.

Peptide Antimicrobial Agents

Cathelicidins comprise a family of mammalian proteins containing a C-terminal cat- ionic antimicrobial domain that becomes active af- ter being freed from the N-terminal cathelin por- tion of the holoprotein. Many other members of this family have been identified since the first cathelicidin sequences were reported 10 years ago. The mature peptides generally show a wide spec- trum of antimicrobial activity and, more recently, some of them have also been found to exert other biological activities. The human cathelicidin pep- tide LL-37 is chemotactic for neutrophils, mono- cytes, mast cells, and T cells; induces degranula- tion of mast cells; alters transcriptional responses in macrophages; and stimulates wound vasculariza- tion and re-epithelialization of healing skin. The porcine PR-39 has also been involved in a variety of processes, including promotion of wound repair, induction of angiogenesis, neutrophils, chemo- taxis, and inhibition of the phagocyte NADPH ox- idase activity, whereas the bovine BMAP-28 in- duces apoptosis in transformed cell lines and acti- vated lymphocytes and may thus help with clearance of unwanted cells at inflammation sites. These multiple actions provide evidence for active participation of cathelicidin peptides in the regula- tion of the antimicrobial host defenses. J. Leukoc. Biol. 75: 000-000; 2004.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0403147

Cathelicidins, multifunctional peptides of the innate immunity

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2895%2901050-O

Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain

The cathelicidin peptides comprise one of several families of antimicrobial peptides that are found in neutrophils and epithelia as components of the early host defenses of mammals against infection. All cathelicidin family members are synthesized and stored in cells as two-domain proteins. These are split on demand to produce a cathelin protein and an antimicrobial peptide. Accumulating evidence indicates that both the cathelin portion and the C-terminal peptide exert biological activities connected with host protection. This review presents an overview of the structure and biology of cathelicidins and discusses recent progress in cathelicidin research with emphasis on the functional properties and role in host defense of the human cathelicidin hCAP18/LL-37. Although investigators initially concentrated their attention on antibiotic activity, it is becoming clear now that LL-37 is a multifunctional molecule that may mediate various host responses, and thus represents an essential component of the innate immune system in humans.

/pdf/the-role-of-cathelicidins-in-the-innate-host-defenses-of-3854uud9hs.pdf

The Role of Cathelicidins in the Innate Host Defenses of Mammals

Identification of CRAMP, a Cathelin-related Antimicrobial Peptide Expressed in the Embryonic and Adult Mouse

Cathelicidins are a numerous group of mammalian proteins that carry diverse antimicrobial peptides at the C-terminus of a highly conserved preproregion. These peptides, which become active when released from the proregion, display a remarkable variety of sizes, sequences, and structures, and in fact comprise representatives of all the structural groups in which the known antimicrobial peptides have been classified. Most of the cathelicidin-derived peptides exert a broad spectrum and potent antimicrobial activity and also bind to lipopolysaccharide and neutralize its effects. In addition, some of them have recently been shown to exert other activities and might participate in host defense also by virtue of their ability to induce expression of molecules involved in a variety of biological processes. This review is aimed at providing a general overview of the cathelicidins and of the peptides derived therefrom, with emphasis on aspects such as structure, biological activities in vitro and in vivo, and structure/activity relationship studies.

Margherita Zanetti

Papers

Cathelicidins, multifunctional peptides of the innate immunity

Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain

The Role of Cathelicidins in the Innate Host Defenses of Mammals

Identification of CRAMP, a Cathelin-related Antimicrobial Peptide Expressed in the Embryonic and Adult Mouse

Structural features and biological activities of the cathelicidin-derived antimicrobial peptides.