Activities of Ceragenin CSA-13 Against Established Biofilms in an In Vitro Model of Catheter Decolonization

Pollard, Jacob; Wright, Jonathan O.; Feng, Yingbin; Geng, Dianliang; Genberg, Carl; Savage, Paul B.

doi:10.2174/187152109789760225

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…Our results agree with previous results of Pollard et al. (). Using colony counting, they studied the effect of CSA‐13 on established biofilms formed by P. aeruginosa in the CDC bioreactor.…”

Section: Discussionsupporting

confidence: 94%

“…As previously reported ), concentrations of CSA-13 active on sessile cells were much higher than those active on planktonic cultures (MIC 6-12 mg/L for PAO1 and 3 mg/L for ATCC 15442). Our results agree with previous results of Pollard et al (2009). Using colony counting, they studied the effect of CSA-13 on established biofilms formed by P. aeruginosa in the CDC bioreactor.…”

Section: Discussionsupporting

confidence: 92%

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Study of the effect of antimicrobial peptide mimic, CSA‐13, on an established biofilm formed by Pseudomonas aeruginosa

et al. 2013

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The formation of a Pseudomonas aeruginosa biofilm, a complex structure enclosing bacterial cells in an extracellular polymeric matrix, is responsible for persistent infections in cystic fibrosis patients leading to a high rate of morbidity and mortality. The protective environment created by the tridimensional structure reduces the susceptibility of the bacteria to conventional antibiotherapy. Cationic steroid antibiotics (CSA)-13, a nonpeptide mimic of antimicrobial peptides with antibacterial activity on planktonic cultures, was evaluated for its ability to interact with sessile cells. Using confocal laser scanning microscopy, we demonstrated that the drug damaged bacteria within an established biofilm showing that penetration did not limit the activity of this antimicrobial agent against a biofilm. When biofilms were grown during exposure to shear forces and to a continuous medium flow allowing the development of robust structures with a complex architecture, CSA-13 reached the bacteria entrapped in the biofilm within 30 min. The permeabilizing effect of CSA-13 could be associated with the death of the bacteria. In static conditions, the compound did not perturb the architecture of the biofilm. This study confirms the potential of CSA-13 as a new strategy to combat persistent infections involving biofilms formed by P. aeruginosa.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 92%

Study of the effect of antimicrobial peptide mimic, CSA‐13, on an established biofilm formed by Pseudomonas aeruginosa

et al. 2013

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“…Minimum bactericidal concentration (MBC) determinations were performed in the buffers used in the depolarization studies and were based on a broth microdilution method described previously (19). Briefly, after incubation with incrementally varied concentrations of the ceragenins for 24 h, MBCs were determined by plating 100 l of each sample on tryptic soy agar (TSA).…”

Section: Methodsmentioning

confidence: 99%

Depolarization, Bacterial Membrane Composition, and the Antimicrobial Action of Ceragenins

Epand

Pollard

Wright

et al. 2010

Antimicrob Agents Chemother

170

158

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Ceragenins are cholic acid-derived antimicrobial agents that mimic the activity of endogenous antimicrobial peptides. Ceragenins target bacterial membranes, yet the consequences of these interactions have not been fully elucidated. The role of the outer membrane in allowing access of the ceragenins to the cytoplasmic membrane of Gram-negative bacteria was studied using the ML-35p mutant strain of Escherichia coli that has been engineered to allow independent monitoring of small-molecule flux across the inner and outer membranes. The ceragenins CSA-8, CSA-13, and CSA-54 permeabilize the outer membrane of this bacterium, suggesting that the outer membrane does not play a major role in preventing the access of these agents to the cytoplasmic membrane. However, only the most potent of these ceragenins, CSA-13, was able to permeabilize the inner membrane. Interestingly, neither CSA-8 nor CSA-54 caused inner membrane permeabilization over a 30-min period, even at concentrations well above those required for bacterial toxicity. To further assess the role of membrane interactions, we measured membrane depolarization in Gram-positive bacteria with different membrane lipid compositions, as well as in Gram-negative bacteria. We found greatly increased membrane depolarization at the minimal bactericidal concentration of the ceragenins for bacterial species containing a high concentration of phosphatidylethanolamine or uncharged lipids in their cytoplasmic membranes. Although membrane lipid composition affected bactericidal efficiency, membrane depolarization was sufficient to cause lethality, providing that agents could access the cytoplasmic membrane. Consequently, we propose that in targeting bacterial cytoplasmic membranes, focus be placed on membrane depolarization as an indicator of potency.

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“…Pollard et al [82] compared the antibiofilm activity of CSA-13 to ciprofloxacin with established bacterial biofilms in a bioreactor developed at the Centers for Disease Control. CSA-13 proved to be better than ciprofloxacin against biofilms formed from methicillinresistant S. aureus.…”

Section: Antibiofilm Activitymentioning

confidence: 99%

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

Hashemi¹,

Holden²,

DurnaÅ³

et al. 2017

J Antimicrob Agents

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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.

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Activities of Ceragenin CSA-13 Against Established Biofilms in an In Vitro Model of Catheter Decolonization

Cited by 18 publications

References 33 publications

Study of the effect of antimicrobial peptide mimic, CSA‐13, on an established biofilm formed by Pseudomonas aeruginosa

Study of the effect of antimicrobial peptide mimic, CSA‐13, on an established biofilm formed by Pseudomonas aeruginosa

Depolarization, Bacterial Membrane Composition, and the Antimicrobial Action of Ceragenins

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

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