Developing ceragenins as a new broad-spectrum therapeutic tool against sepsis-causing bacteria

The increasing prevalence of infections caused by microorganisms resistant to antibiotics is a significant public health concern. Particularly, Gram-negative bacteria, including Pseudomonas aeruginosa, Escherichia coli and Stenotrophomonas maltophilia, are pathogens of high clinical importance causing severe and life-threatening nosocomial infections such as ventilator-associated pneumonia (VAP), bloodstream infections, catheter-associated urinary tract infections and burn wound infections. Ceragenins (CSAs) are promising small-molecule, lipid mimics of antimicrobial peptides with similar physicochemical properties, while being less toxic and more stable under physiological conditions. This study aims to explore the effectiveness of ceragenins against selected bacteria, especially Gram-negative rods, both in in vitro and in vivo settings. Methods The antibacterial activity of ceragenins was evaluated using both single and combinatorial treatments with clinically-relevant antibiotics. Cytotoxicity of applied treatments was evaluated using colorimetric and microscopic methods in cell culture conditions. The therapeutic effectiveness against E. coli was investigated using a mouse model of urinary tract infection followed by analysis of nanomechanical properties of collected bladder tissues. Results Collected data showed that ceragenins at low concentrations are highly active against clinical strains of P. aeruginosa, S. maltophilia and E. coli, both when used alone and combined with other antimicrobials. Ceragenins also show low potential for development of drug resistance and controlled toxicity, confirmed also in in vivo settings. CSA-13 was also noted to display a preventive role against bacteria-induced tissue damage and potentially promote the restoration of microenvironment with biophysical features unfavorable for bacterial growth and spreading. Conclusion Our data suggest that ceragenins are promising agents for future development of new methods for treatment of nosocomial infections.