Journal Article

Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum

Robert Bucki, Audra Goach Sostarecz, Fitzroy J. Byfield, Paul B. Savage and Paul A. Janmey

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 60, issue 3, pages 535-545
Published in print September 2007 | ISSN: 0305-7453
Published online June 2007 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkm218
Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum

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  • Medical Oncology
  • Critical Care

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Objectives

The goal of this study was to evaluate the effects of DNA and F-actin [polyanions present in high concentration in cystic fibrosis (CF) airway fluid] on the antibacterial activities of the cationic steroid antibiotic CSA-13 and the cationic peptides LL37, WLBU2 and HB71.

Methods

Light scattering intensity was used to evaluate the aggregation of DNA and F-actin by the cationic antibacterial agents. Bacterial killing assays, atomic force microscopy, determination of MIC values and bacterial load of CF sputa were used to determine the bactericidal activity. Inhibition of nuclear factor-κB (NF-κB) translocation in human aorta endothelial cells (HAECs) was quantified as an assay of anti-inflammatory action.

Results

CSA-13 is significantly more effective than cationic antibacterial peptides against kanamycin-resistant Pseudomonas aeruginosa and less susceptible to inactivation by DNA or F-actin. The concentration of CSA-13 sufficient to decrease the CF sputa bacteria load by ∼90% is at least 10 times lower than that at which CSA-13 formed aggregates with DNA or F-actin. Both CSA-13 and LL37 prevent lipopolysaccharide-induced translocation of NF-κB in HAEC, thereby suggesting that these antibacterial molecules might prevent systemic inflammation caused by bacterial wall components.

Conclusions

Charge-based interactions that strongly inhibit the antibacterial activity of host cationic antibacterial peptides present in CF sputa have significantly less effect on molecules from the ceragenin family such as CSA-13 due in part to their smaller net charge and distribution of this charge over a hydrophobic scaffold. CSA molecules therefore have potential for the treatment of chronic infections and inflammation that occur in CF airways and other settings in which extracellular polyanions accumulate.

Keywords: cathelicidin; lipopolysaccharide; nuclear factor-κB

Journal Article.  5305 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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