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

AbstractOBJECTIVES:
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-kappaB (NF-kappaB) 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 approximately 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-kappaB 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.
AuthorsRobert Bucki, Audra Goach Sostarecz, Fitzroy J Byfield, Paul B Savage, Paul A Janmey
JournalThe Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 60 Issue 3 Pg. 535-45 (Sep 2007) ISSN: 0305-7453 [Print] England
PMID17584802 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Actins
  • Anti-Bacterial Agents
  • Electrolytes
  • Lipopolysaccharides
  • Peptides
  • Steroids
  • Teichoic Acids
  • ceragenin CSA-13
  • lipoteichoic acid
  • DNA
  • Deoxyribonuclease I
Topics
  • Actins (pharmacology)
  • Adult
  • Amino Acid Sequence
  • Anti-Bacterial Agents (antagonists & inhibitors, chemistry, pharmacology)
  • Bacteria (drug effects, ultrastructure)
  • Cell Line
  • Cystic Fibrosis (drug therapy, microbiology)
  • DNA (pharmacology)
  • Deoxyribonuclease I (metabolism)
  • Drug Resistance, Bacterial
  • Electrolytes (pharmacology)
  • Endothelial Cells
  • Erythrocytes (drug effects)
  • Hemolysis (drug effects)
  • Humans
  • Lipopolysaccharides (pharmacology)
  • Microbial Sensitivity Tests
  • Microscopy, Atomic Force
  • Peptides (chemistry, pharmacology)
  • Sputum (microbiology)
  • Steroids (antagonists & inhibitors, chemistry, pharmacology)
  • Teichoic Acids (pharmacology)

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