New β-Lactam Antibiotics and Ceragenins – A Study to Assess Their Potential in Treatment of Infections Caused by Multidrug-Resistant Strains of Pseudomonas aeruginosa

Abstract

Paulina Paprocka,1 Bonita Durnaś,1,2 Angelika Mańkowska,1 Karol Skłodowski,3 Grzegorz Król,1 Magdalena Zakrzewska,3 Michał Czarnowski,3 Patrycja Kot,1 Kamila Fortunka,1 Stanisław Góźdź,2 Paul B Savage,4 Robert Bucki1,3 1Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, Kielce, Poland; 2Holy Cross Oncology Center of Kielce, Kielce, Poland; 3Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland; 4Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USACorrespondence: Robert Bucki Tel [phone]Fax [phone]Email [email protected]: The increasing number of infections caused by antibiotic resistant strains of Pseudomonas aeruginosa posed a very serious challenge for clinical practice. This standing is driving scientists to develop new antibiotics against these microorganisms.Methods: In this study, we measured the MIC/MBC values and estimated the ability of tested molecules to prevent bacterial biofilm formation to explore the effectiveness of β-lactam antibiotics ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, and ceragenins CSA-13, CSA-44, and CSA-131 against 150 clinical isolates of Pseudomonas aeruginosa that were divided into five groups, based on their antibiotic resistance profiles to beta-lactams. Selected strains of microorganisms from each group were also subjected to prolonged incubations (20 passages) with ceragenins to probe the development of resistance towards those molecules. Cytotoxicity of tested ceragenins was evaluated using human red blood cell (RBCs) hemolysis and microscopy observations of human lung epithelial A549 cells after ceragenin treatment. Poloxamer 407 (pluronic F-127) at concentrations ranging from 0.5% to 5% was tested as a potential drug delivery substrate to reduce ceragenin toxicity.Results: Collected data proved that ceragenins at low concentrations are highly active against clinical strains of Pseudomonas aeruginosa regardless of their resistance mechanisms to conventional antibiotics. Ceragenins also show low potential for resistance development, high antibiofilm activity, and controlled toxicity when used together with poloxamer 407.Conclusion: This data strongly supports the need for further study directed to develop this group of molecules as new antibiotics to fighting infections caused by antibiotic resistant strains of Pseudomonas aeruginosa.Keywords: ceragenin, antibacterial agents, Pseudomonas aeruginosa, antibiotic resistant bacteria, new antibiotics

Keywords

• ceragenin
• antibacterial agents
• pseudomonas aeruginosa
• antibiotic resistant bacteria
• new antibiotics.