Cathelicidins and functional analogues as antisepsis molecules

Abstract

The emergence of antibiotic-resistant bacteria together with the limited success of sepsis therapeutics has lead to an urgent need for the development of alternative strategies for the treatment of systemic inflammatory response syndrome and related disorders. Immunomodulatory compounds that do not target the pathogen directly (therefore limiting the development of pathogen resistance), and target multiple inflammatory mediators, are attractive candidates as novel therapeutics. Cationic host defence peptides such as cathelicidins have been demonstrated to be selectively immunomodulatory in that they can confer anti-infective immunity and modulate the inflammatory cascade through multiple points of intervention. The human cathelicidin LL-37, for example, has modest direct antimicrobial activity under physiological conditions, but has been demonstrated to have potent antiendotoxin activity in animal models, as well as the ability to resolve certain bacterial infections. A novel synthetic immunomodulatory peptide, IDR-1, built on this same theme has no direct antimicrobial activity, but is effective in restricting many types of infection, while limiting pro-inflammatory responses. The ability of these peptides to selectively suppress harmful pro-inflammatory responses, while maintaining beneficial infection-fighting components of host innate defences makes them a good model for antisepsis therapies that merit further investigation.

New Antiseptic Peptides To Protect against Endotoxin-Mediated Shock

“…In In recent years, LPS-neutralizing antimicrobial peptides have been in the focus of sepsis research (18)(19)(20)(21)(22)28). In most cases, however, the applied excess concentration ratio of peptide to LPS, necessary for sufficiently high LPS inactivation, was in the range of 1,000, or even higher, thus being insufficiently selective for LPS with respect to cytotoxic effects against physiological mammalian cells.…”

An estimate of the global reduction in mortality rates through doubling vitamin D levels

“…However, an ecological study offers reasonable evidence that higher serum 25(OH)D level is associated with reduced risk of sepsis in the United States, on the basis of racial, seasonal and geographic variations (Grant, 2009e). The mechanism is induction of cathelicidin by vitamin D (Mookherjee et al, 2007).…”

Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism

“…Moreover, their microbial killing and immune modulating activities are more potent than most of the other AMPs characterized thus far. Because of their small size, low toxicity, high stability, and diverse mechanisms, they are deemed attractive candidates for anti-infective agent development (18,19). There are three cathelicidin analogs being tested in clinical trials: Iseganan, Omiganan, and MBI 594AN (20).…”