Epithelial peptide antibiotics

Surfaces of higher eukaryotes such as plants, invertebrates, and vertebrates, including humans, are normally covered with microorganisms but usually are not infected by them. The reason, apart from physical barriers, is the production of gene-encoded antimicrobial peptides by epithelial cells. Many novel antimicrobial peptides have been discovered recently in the epithelia of plants, insects, amphibians, and cattle, and, more recently, also in humans. In situ hybridization studies indicate a rather organ-specific expression of the genes for peptide antibiotics, which, due to their antimicrobial spectrum and conditions of expression, may also define the physiologic microflora. Some epithelial antimicrobial peptides are constitutively expressed; others are inducible, either by the presence of microorganisms via as of yet not well characterized elicitor receptors or by endogenous proinflammatory cytokines. Most antimicrobial peptides kill microorganisms by forming pores in the cell membrane, and the sensitivity of some peptide antibiotics towards cholesterol, a major mammalian cell membrane constituent, may indicate why these peptide antibiotics are not toxic for mammalian cells. Thus, it seems to be difficult for microorganisms to acquire resistance, making these peptides very attractive for therapeutic use as antibiotics. The first clinical studies are very promising, and after solving the problems of a large-scale biotechnical synthesis, which is more complicated due to the principally suicidal activity of these peptides, a number of new natural structure-based peptides may be developed. Furthermore, discovery of the inducibility of many antimicrobial peptides may also lead to the development of compounds that elicit epithelial defense reactions by stimulating the synthesis of endogenous peptide antibiotics.