Ceragenins: Cholic Acid-Based Mimics of Antimicrobial Peptides

Abstract

The prevalence of drug-resistant bacteria drives the quest for new antimicrobials, including those that are not expected to readily engender resistance. One option is to mimic Nature's most ubiquitous means of controlling bacterial growth, antimicrobial peptides, which have evolved over eons. In general, bacteria remain susceptible to these peptides. Human antimicrobial peptides play a central role in innate immunity, and deficiencies in these peptides have been tied to increased rates of infection. However, clinical use of antimicrobial peptides is hampered by issues of cost and stability. The development of nonpeptide mimics of antimicrobial peptides may provide the best of both worlds: a means of using the same mechanism chosen by Nature to control bacterial growth without the problems associated with peptide therapeutics. The ceragenins were developed to mimic the cationic, facially amphiphilic structures of most antimicrobial peptides. These compounds reproduce the required morphology using a bile-acid scaffolding and appended amine groups. The resulting compounds are actively bactericidal against both gram-positive and gram-negative organisms, including drug-resistant bacteria. This antimicrobial activity originates from selective association of the ceragenins with negatively charged bacterial membrane components. Association has been studied with synthetic models of bacterial membrane components, with bacterial lipopolysaccharide, with vesicles derived from bacterial phospholipids, and with whole cells. Comparisons of the antimicrobial activities of ceragenins and representative antimicrobial peptides suggest that these classes of compounds share a mechanism of action. Rapid membrane depolarization is caused by both classes as well as blebbing of bacterial membranes. Bacteria express the same genes in response to both classes of compounds. On the basis of the antibacterial activities of ceragenins and preliminary in vivo studies, we expect these compounds to find use in augmenting or replacing antimicrobial peptides in treating human disease.

Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells

“…11 Modified antimicrobial LL-37 peptides, such as FF/CAP18, and a synthetic antimicrobial peptide mimic, ceragenin CSA-13, also have the potential to suppress growth of colon cancer cells. [12][13][14][15] It was found that expression of LL-37 is reduced during progression of stomach cancer from atrophic gastritis to adenocarcinoma. The modified antimicrobial peptide FF/CAP18 exerts antiproliferative effects on the SAS-H1 squamous carcinoma cell line.…”

Core&ndash;shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins

“…[41][42][43][44][45][46] Significant membrane activity of CSAs results in bacterial membrane permeabilization and depolarization. 44,47 Previous studies indicate that antimicrobial activity of ceragenins against Gram-negative bacteria is usually lower than the effects against Gram-positive species. The authors suggest that differences in CSA activities are caused by a high content of phosphatidylethanolamine, which might inhibit cationic steroids from binding as well to some bacterial membranes.…”

Neutrophil extracellular traps as the main source of eDNA

“…Importantly, elevated eDNA and NET levels and their accumulation in biological fluids is a factor activating innate immune responses, which considerably affect the development of such diseases as asthma and chronic obstructive pulmonary disease [48], periodontitis [49], antineutrophil cytoplasmic antibody-associated vasculitis (AAV) [29], or cancerassociated thrombosis [50]. Quantitative analysis of the physical chemistry of polyelectrolytes has been useful for designing possible countermeasures to release endogenous antimicrobial peptides trapped in the polyelectrolyte bundles present in purulent fluids [5,45,[51][52][53][54][55][56]. Better penetration through this complex network might be achieved using a nanotechnology approach.…”