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Antibiotic peptides from higher eukaryotes: biology and applications

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Abstract

Gene-encoded antibiotic peptides are increasingly being recognized as effector molecules of host defense in plants and animals. Studies of antimicrobial peptides are providing new insights into the dynamic interactions between microbes and their hosts, and are generating new paradigms for the pathogenesis and treatment of diseases. Because antimicrobial peptides of higher eukaryotes differ structurally from conventional antibiotics produced by bacteria and fungi, they offer novel templates for pharmaceutical compounds that could be effective against increasingly resistant microbes.

Section snippets

Distribution of antimicrobial peptides

Antimicrobial peptides are widely distributed in plants and animals. Epithelial surfaces of vertebrates secrete antimicrobial peptides from both barrier epithelia and glandular structures1, 2, 3, 4. Phagocytic cells contain several types of storage organelles (granules) for microbicidal substances and digestive enzymes5, 6. In the process of phagocytosis, some of these granules empty their contents onto ingested microbes, generating a killing vacuole that has very high concentrations of

Structures and mechanism of action

Almost all antimicrobial peptides are cationic and amphipathic. The simplest antimicrobial peptide structures (Table 1) whose mechanism of action has been investigated are either α helices or β hairpins (Fig. 1). Both types of peptides can form transmembrane channels. The length of a simple α helix is ∼1.5 Å per amino acid residue, whereas that of a β hairpin is ∼3.5 Å per two residues. Because the hydrocarbon core of the phospholipid membrane is ∼30 Å across, it takes about 20 amino acids to

Regulation of synthesis and release

In invertebrates and plants – organisms that lack adaptive immunity – antimicrobial peptides constitute a major component of host defense14, 25, 26. Many of the plant and invertebrate peptides (e.g. insect defensins and plant defensins) resemble their vertebrate counterparts in structure and function, but a comprehensive evolutionary lineage has not yet been established. Both plants and invertebrates induce the synthesis of antimicrobial peptides in response to infection. The signaling pathways

Spectrum of activity

Many antimicrobial peptides have activity against Gram-positive and Gram-negative bacteria, yeasts and fungi, and even certain enveloped viruses and protozoa. Other peptides are more restricted in their spectrum. Even minor variations in peptide structure can influence activity, and a systematic understanding of the relationship between peptide structure and activity is an important area for future investigations. Evidence is accumulating that many peptides act synergistically with larger

Biological role and consequences of defects in the function of antimicrobial peptides

Convincing evidence for the role of antimicrobial peptides has been obtained in plants, where genetic transplantation of antimicrobial peptides from one plant species to another can confer resistance to selected plant pathogens14. In insects, injury or infection elicits the production of antimicrobial peptides in the fat body (an equivalent of the vertebrate liver) and within a few hours renders the hemolymph (an equivalent of blood) antimicrobial. At least two distinct pathways participate in

Applications of antimicrobial peptides

Despite the problem of increasing microbial resistance to existing medications, few new structural classes of antibiotics have reached the pharmacy during the past decade. The many different antimicrobial peptide structures found in a variety of biological settings give rise to optimism that some of these compounds will prove useful as therapeutic antibiotics41. The main problems in the development of such antibiotics include concerns about tissue penetration, potential toxicities and the cost

The outstanding questions

  • What roles do individual antimicrobial peptides play in specific infections of the epithelia and deeper tissues?

  • What structural determinants allow antimicrobial peptides to exert activity against specific microbes?

  • In addition to membranes, what are the other targets of antimicrobial peptides?

  • Do antimicrobial peptides regulate inflammation or the adaptive immune response in vivo?

  • How do infections induce the production of antimicrobial peptides in Drosophila, in mammals and in human tissues?

Glossary

Glossary

Acute phase response
– The altered pattern of protein synthesis by infected vertebrate animals that makes the host more resistant to infection. Synthesis of some proteins is increased and others decreased. The response is regulated by the transcriptional regulators nuclear factor κB (NF-κB), nuclear factor interleukin 6 (NF-IL6) and others.
α-helical peptide
– A peptide the structure of which comprises a helical backbone with the amino acid side chains directed away from the center of the helix.

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