Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Abstract

Ceragenins are small molecule mimics of endogenous antimicrobial peptides (AMPs), and as such display broadspectrum antimicrobial activity. These molecules are derived from a common bile acid and can be prepared at a large scale. Because ceragenins are not peptide based, they are not substrates for proteases. Gram-negative and positive bacteria are susceptible to ceragenins, including drug resistant organisms. Although ceragenins and colistin have common features, ceragenins retain full antibacterial activity against colistin-resistant Gram-negative bacteria. Bactericidal activity of ceragenins involves selective association with bacterial membranes followed by membrane depolarization. Due to this mechanism of action, which provides bactericidal activity against sessile bacteria, ceragenins eradicate established biofilms. Lipid-enveloped viruses (e.g. vaccinia) are deactivated by ceragenins, and topical application of a lead ceragenin decreases transmission of the virus in skin in a murine model. More recently, the activities of ceragenins against fungal pathogens have been reported, with minimum inhibition concentrations comparable to clinically used anti-fungal agents. In addition to antimicrobial activities, ceragenins have been shown to display some of the "secondary" activities attributed to AMPs. In vivo use of ceragenins to eradicate biofilms, prevent infection and accelerate bone growth demonstrate some of the types of applications in which ceragenins may be used to augment or replace activities of endogenous AMPs.

Lysozyme increases bactericidal activity of ceragenin CSA-13 against Bacillus subtilis

“…The combination could also be considered in the development of products for wound healing for topical applications. Ceragenins, with their: (i) strong antimicrobial activity against a variety of microorganisms, even Bacillus spores, (ii) ability to inhibit biofilm formation, (iii) biological activity in body fluids, (iv) good safety profile, and (v) anti-inflammatory properties, could be excellent candidates for potential use also in such infections as endophthalmitis [39]. Endophthalmitis following ocular trauma can be caused by a wide range of bacteria and fungi, including multidrug-resistant organisms.…”

Ceragenins as non-peptide mimics of endogenous antimicrobial peptides

“…Due to the fact that they are not peptide-based, they are not substrates for ubiquitous proteases. Preparation and purification of ceragenins on a large scale is relatively straightforward, they are stable under physiological conditions and even long-term storage in solution does not reduce their antibiotic activities [37,38]. As ceragenins follow the amphiphilic structure of AMPs they display a similar spectrum of activity against bacterial, fungi and lipid-enveloped viruses [39].…”

“…Ceragenins and AMPs, on the other hand, target the bacterial membrane, and are able to kill bacterial and fungal cells regardless of whether they are rapidly growing, dividing, or sessile [83]. In addition, the relatively small size of ceragenins allows them to penetrate the extracellular matrix of biofilms and gain access to the cells within [38]. A comparative study of ceragenins with ciprofloxacin indicated that a much lower concentration of CSA-13 was required to eradicate an established biofilm consisting of a meticillin-resistant strain of S. aureus in comparison with ciprofloxacin.…”

Antimicrobial peptides from the edible insect Musca domestica and their preservation effect on chilled pork

“…Although they possess diverse structures, most AMPs share common characteristics such as short amino acids and positive charges (Li et al, ). AMPs are also known as compounds with broad‐spectrum antimicrobial activity against gram‐negative and gram‐positive bacteria, fungi, and lipid‐enveloped viruses (Hashemi, Holden, Durnas, Bucki, & Savage, ). Furthermore, they retain activity against antibiotic‐resistant strains and do not readily elicit resistance (Brogden & Brogden, ).…”

“…gram-positive bacteria, fungi, and lipid-enveloped viruses (Hashemi, Holden, Durnas, Bucki, & Savage, 2017). Furthermore, they retain activity against antibiotic-resistant strains and do not readily elicit resistance (Brogden & Brogden, 2011).…”