Antibacterial and Antifungal Activities of Poloxamer Micelles Containing Ceragenin CSA-131 on Ciliated Tissues

Abstract

Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated with cystic fibrosis. A characteristic of an optimal therapeutic for use in the lungs and trachea is the exertion of potent antimicrobial activities without damaging the cilia that play a critical role in these tissues. In previous work, potent antimicrobial activities of ceragenin CSA-131 have been reported; however, we found in ex vivo studies that this ceragenin, at concentrations necessary to eradicate established biofilms, also causes loss of cilia function. By formulating CSA-131 in poloxamer micelles, cilia damage was eliminated and antimicrobial activity was unaffected. The ability of CSA-131, formulated with a poloxamer, to reduce the populations of fungal pathogens in tracheal and lung tissue was also observed in ex vivo studies. These findings suggest that CSA-131, formulated in micelles, may act as a potential therapeutic for polymicrobial and biofilm-related infections in the lung and trachea.

Proteomic Analysis of Resistance of Gram-Negative Bacteria to Chlorhexidine and Impacts on Susceptibility to Colistin, Antimicrobial Peptides, and Ceragenins

“…Notably, most endogenous antimicrobial peptides (AMPs, representative sequences are shown in Figure 1) also display these features: cationic groups juxtaposed with hydrophobic side chains (Hashemi et al, 2017a, 2018a). We recently reported (Hashemi et al, 2017c) that highly colistin-resistant bacteria are susceptible to both AMPs and non-peptide mimics of AMPs, termed ceragenins (representative structures are shown in Figure 1) (Hashemi et al, 2017b, 2018b,c,d). This finding led to the question of whether generation of chlorhexidine resistance results in cross resistance to ceragenins and AMPs.…”

Fungal infection models: Current progress ofex vivomethods

“…In the study proposed by Hashemi et al, lung and tracheal pig tissues were used as infection models to evaluate the fungal efficacy of formulations. Besides the antifungal potential, the impact of the formulations on the ciliated tissue is an important factor, since the cilia on these tissues play a critical role in removing particulate matter from the lung and trachea, which was also evaluated in this study.…”

“…Besides the antifungal potential, the impact of the formulations on the ciliated tissue is an important factor, since the cilia on these tissues play a critical role in removing particulate matter from the lung and trachea, which was also evaluated in this study. The presence of cilia suggests that the epithelial and goblet cells were also unaffected by treatment …”

Susceptibility of Multidrug-Resistant Bacteria, Isolated from Water and Plants in Nigeria, to Ceragenins

“…Remaining solution was removed from each well and remaining dye in the wells was then quantified with a microtiter plate reader at 490 nm. Optical density results of test wells were compared with controls to determine the percent of biofilm remaining in each [23].…”