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

Marjan Hashemi,Shawn Gubler,Shenglou Deng,Paul Savage,Brett Holden,Carl Genberg,John Wilson,Brian Hilton,Tania Nance,Maddison Taylor,Jordan Coburn

doi:10.3390/molecules23030596

Marjan Hashemi, Shawn Gubler + Show 9 more

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https://doi.org/10.3390/molecules23030596

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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.

Highlights

Ceragenins were developed as mimics of antimicrobial peptides (AMPs), and, as such, display the broad-spectrum antibacterial and antifungal activities common to most AMPs [1,2]
To observe the impact of biofilm-based pluronic micelles on ceragenins activity and to the optimize formulation for use in treating infections in the lung, we studied impactceragenin of a lead formulation for use in treating biofilm-based infections in the lung, we studied the impact of a lead ceragenin, CSA-131, with and without pluronic on cilia beating and the inhibition of bacterial and ceragenin, CSA-131, withoutand pluronic on ciliaexplants
CiliaThese beating intact,suggest and thethat pluronic has no impact impact onhigh the concentrations antimicrobial activities of leaves results the formulation of on the antimicrobial activities of. These results suggest that the formulation of ceragenin ceragenin CSA-131 in pluronic micelles may allow use of high concentrations of this antimicrobial, CSA-131 in allownegatively use of highimpacting concentrations of this antimicrobial, sufficient to sufficient topluronic eliminatemicelles biofilmsmay without cilia function

Summary

Introduction

Ceragenins were developed as mimics of antimicrobial peptides (AMPs), and, as such, display the broad-spectrum antibacterial and antifungal activities common to most AMPs [1,2] These activities extend to drug-resistant organisms [3,4] and to established biofilms [5,6,7]. We have shown that ceragenins bind to bacterial membrane surfaces even in the presence of larger surface areas of mammalian cells [8] This selectivity likely contributes to the antimicrobial activities of ceragenin in many tissues, without adverse effects, including the peritoneal cavity [9], in bone fractures [10], and on bone [11,12] and lung-associated [13] medical devices. In biofilm form, microorganisms enter a sessile state [14] in which

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