In vitro evaluation of the potential for resistance development to ceragenin CSA-13
| Autor: | Bobbie Christiansen, Vinod Chaudhary, Jonathan P. Wright, Paul B. Savage, Jason Snarr, Jake E. Pollard, Jacob D. Jennings, Hannah Shaw, Russell E. Bishop, Wenyi Jia |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Acinetobacter baumannii
Microbiology (medical) Staphylococcus aureus Gram-positive bacteria Antimicrobial peptides Microbial Sensitivity Tests medicine.disease_cause Mass Spectrometry Microbiology chemistry.chemical_compound Anti-Infective Agents Ceragenin Drug Resistance Bacterial medicine Pharmacology (medical) Original Research Pharmacology biology Cell Membrane Antimicrobial biology.organism_classification Ciprofloxacin Lipid A Infectious Diseases chemistry Pseudomonas aeruginosa Colistin Vancomycin Steroids medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 67:2665-2672 |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | Though most bacteria remain susceptible to endogenous antimicrobial peptides, specific resistance mechanisms are known. As mimics of antimicrobial peptides, ceragenins were expected to retain antibacterial activity against Gram-positive and -negative bacteria, even after prolonged exposure. Serial passaging of bacteria to a lead ceragenin, CSA-13, was performed with representative pathogenic bacteria. Ciprofloxacin, vancomycin and colistin were used as comparators. The mechanisms of resistance in Gram-negative bacteria were elucidated.Susceptible strains of Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii were serially exposed to CSA-13 and comparators for 30 passages. MIC values were monitored. Alterations in the Gram-negative bacterial membrane composition were characterized via mass spectrometry and the susceptibility of antimicrobial-peptide-resistant mutants to CSA-13 was evaluated.S. aureus became highly resistant to ciprofloxacin after20 passages. After 30 passages, the MIC values of vancomycin and CSA-13 for S. aureus increased 9- and 3-fold, respectively. The Gram-negative organisms became highly resistant to ciprofloxacin after20 passages. MIC values of colistin for P. aeruginosa and A. baumannii increased to ≥100 mg/L after 20 passages. MIC values of CSA-13 increased to ∼20-30 mg/L and plateaued over the course of the experiment. Bacteria resistant to CSA-13 displayed lipid A modifications that are found in organisms resistant to antimicrobial peptides.CSA-13 retained potent antibacterial activity against S. aureus over the course of 30 serial passages. Resistance generated in Gram-negative bacteria correlates with modifications to the outer membranes of these organisms and was not stable outside of the presence of the antimicrobial. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|