Affiliation:
1. Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada
2. Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference20 articles.
1. Use of the Cell Wall Precursor Lipid II by a Pore-Forming Peptide Antibiotic
2. Bucki, R., A. G. Sostarecz, F. J. Byfield, P. B. Savage, and P. A. Janmey. 2007. Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum. J. Antimicrob. Chemother.60:535-545.
3. Chin, J. N., R. N. Jones, H. S. Sader, P. B. Savage, and M. J. Rybak. 2008. Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa. J. Antimicrob. Chemother.61:365-370.
4. Chongsiriwatana, N. P., and A. E. Barron. 2010. Comparing bacterial membrane interactions of antimicrobial peptides and their mimics. Methods Mol. Biol.618:171-182.
5. Ding, B., Q. Guan, J. P. Walsh, J. S. Boswell, T. W. Winter, E. S. Winter, S. S. Boyd, C. Li, and P. B. Savage. 2002. Correlation of the antibacterial activities of cationic peptide antibiotics and cationic steroid antibiotics. J. Med. Chem.45:663-669.
Cited by
163 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献