1.C.33 The Cathelicidin (Cathelicidin) Family
The Cathelicidin family consists of fairly large (90-220 residue) proteins that are produced by various mammals. They consist of a conserved N-terminal propeptide domain of about 100 residues and a variable C-terminal antimicrobial peptide domain (12-100 aas). They are often processed to small (about 18 residue) amphipathic peptides that insert into biological membranes and exert antimicrobial activities against both Gram-negative and Gram-positive bacteria, fungi, protozoans and certain enveloped viruses. Some have a broad range of targets while others have a narrow range.
Protegrins, one group of cathelicidins, are arginine- and cysteine-rich peptides that form β-sheets. At least some of these peptides form weakly anion-selective channels in planar phospholipid bilayers, but they form moderately cation-selective channels in planar lipid membranes that contain bacterial lipopolysaccharide. They induce K+ leakage from liposomes and serve the general function of antimicrobial host defense. Arginyl residues in protegrin-1 (Jang et al., 2008) comlpex the lipid phosphoryl moieties to form the toroidal pores (Jang et al., 2008). These authors suggest that this process initiates peptide aggregation on the membrane surface to cause lateral expansion and micelle formation.
PG-1 causes transmembrane pores of the barrel-stave type in the LPS membrane, thus allowing further translocation of the peptide into the inner membrane of gram-negative bacteria to kill the cells. In comparison, the less cationic mutant cannot fully cross the LPS membrane because of weaker electrostatic attractions, thus causing weaker antimicrobial activities. Therefore, strong electrostatic attraction between the peptide and the membrane surface, ensured by having a sufficient number of Arg residues, is essential for potent antimicrobial activities against gram-negative bacteria (Su et al. 2011).
Peptides of the Cathelicidin family resemble tachyplesins from horseshoe crab hemocytes (TC #1.C.34) and vertebrate and protozoan defensins including peptide channel-formers of the Amoebaporin family (TC #1.C.35). Protegrin monomers form β-hairpin structures in solution and dimers in phopholipid micelles. These latter structures may comprise the building blocks for the channels formed from these peptides.
Tryptophan-rich antimicrobial peptides serve as host innate defense mechanisms in eukaryotes (animals and plants). They are active against Gram-negative and Gram-positive bacteria. Some have been shown to interact strongly with negatively charged phospholipid vesicles where they induce efficient dye release (Wei et al., 2006). Their antimicrobial activities may result from interactions with bacterial membranes. These peptides are derived from eukaryotic proteins or are synthetic. Several have been studied. These include indolicidin (ILPWKWPWWPWRR-NH2). The precursor is indolicidin precursor (cathelicidin-4) (TC #1.C.33.1.2). It can be isolated from the cytoplasmic granules of bovine neutrophils. It is active against bacteria, protozoa, fungi and enveloped viruses such as HIV. Other tryptophan-rich peptides include trituticin, pureA, LfcinB, PW2, Pac525 and Pac525rev (Wei et al., 2006).
Novicidin is an 18-residue cationic antimicrobial peptide derived from ovispirin, a cationic peptide which originated from the ovine cathelicidin SMAP-29. Novicidin, however, has been designed to minimize the cytotoxic properties of SMAP-29 and ovisipirin toward achieving potential therapeutic applications.
Dorosz et al. (2010) presented an analysis of membrane interactions and lipid bilayer penetration of novicidin, using an array of biophysical techniques and biomimetic membrane assemblies, complemented by Monte Carlo (MC) simulations. The data indicate that novicidin interacts minimally with zwitterionic bilayers, accounting for its low hemolytic activity. Negatively charged phosphatidylglycerol, on the other hand, plays a significant role in initiating membrane binding of novicidin, and promotes peptide insertion into the interface between the lipid headgroups and the acyl chains. Insertion into bilayers containing negative phospholipids might explain the enhanced antibacterial properties of novicidin. A combination of electrostatic attraction to the lipid/water interface and penetration into the subsurface lipid headgroup region are determinants of activity.
Novicidin forms toroidal pores at high concentrations leading to fairly extensive membrane lipid disturbance (Bertelsen et al. 2012). Peptide binding may first induce leakage at a critical surface concentration, probably through formation of transient pores or transient disruption of the membrane integrity, followed by more extensive membrane disintegration at higher P/L ratios (Nielsen and Otzen 2010).
Peptides, indolicidin, aurein 1.2, magainin II, cecropin A and LL-37 all cause a general acceleration of essential lipid transport processes without altering the overall structure of the lipid membranes or creating organized pore-like structures (Nielsen et al. 2020). Rapid scrambling of the lipid composition associated with enhanced lipid transport may trigger lethal signaling processes and enhance ion transport.
The generalized reaction catalyzed by protegrins, and possibly by other cathelicidin family members is:
Small molecules (in) Small molecules (out)