Potential of ceragenin CSA-13 and its mixture with pluronic F-127 as treatment of topical bacterial infections

Abstract

Aims Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. Methods and Results CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC /MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (−) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). Conclusion These results suggest that CSA-13 may be useful to prevent and treat topical infection. Significance and Impact of the Study Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity.

Ceragenins as Mimics of Endogenous Antimicrobial Peptides

“…The amphiphilic nature of ceragenins allows them to associate well with micelles, and Nagant et al [78] and Leszczynska et al [88] studied the effects of pluronic F-127 on the cytotoxicity of ceragenins. They found that micelles derived from pluronic F-127 decreased cytotoxicity toward eukaryotic cells and possibly improved antimicrobial activities.…”

“…Diagnostic antimicrobial nanoparticles consisting of CSA-124 bound on a silver shell with a maghemite core were successfully synthesized and introduced as a novel multifunctional theranostic conjugate by Hayes et al [88,101]. Confocal imaging showed that the nanoparticles displayed higher selectivity for S. aureus than E. coli.…”

“…CSA-13-colistin combinations proved the most synergystic (54% of tested strains), while CSA-13-tobramycin combinations showed the lowest level of synergistic interactions (25% of tested strains). Bucki et al [88] demonstrated that a combination of CSA-13 with AMPs, including LL-37, lysozyme, lactoferrin and secretory phospholipase A, enhanced antibacterial activity of CSA-13 against bacteria causing topical infections. This observation is consistent with the hypothesis that endogenous AMPs synergize with administered antimicrobials and antibiotics [89].…”

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

“…Previous published reports related to activity of CAPs at infection sites revealed synergism or additive interactions with other host-secreted antibacterial agents. 59,60 Recent studies confirm that ceragenins also exhibit a synergistic effect with other antibacterial agents such as cefepime and ciprofloxacine. 41,61 Ruden et al 23 revealed that silver nanoparticles act synergistically with polymyxin B.…”

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.…”