Rico Schmidt1, Eszter Ostorházi2, Elisabeth Wende1, Daniel Knappe1, Ralf Hoffmann3. 1. Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany. 2. Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary Institute of Laboratory Medicine, Semmelweis University, Budapest, Hungary. 3. Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany hoffmann@chemie.uni-leipzig.de.
Abstract
OBJECTIVES: To evaluate the efficacy of antimicrobial peptide Onc112 in a lethal Escherichia coli infection model and the pharmacokinetics of Onc72 and Onc112 administered intravenously or intraperitoneally in mice. METHODS: Onc72, Onc112 and their major metabolites in blood, kidneys, liver, brain and urine were quantified by MS using multiple reaction monitoring (MRM) and isotope-labelled peptides. RESULTS: Onc112 rescued all animals when administered intraperitoneally at a dose of 2.5 mg/kg and was thus slightly more efficient than Onc72. The MRM method provided limits of quantification in plasma, urine and kidney, liver and brain homogenates of 7-80 μg/L, well below the MICs of 2-4 mg/L. Onc72 and Onc112 reached all organs within 10 min when administered intraperitoneally (5 mg/kg). Their initial concentrations in plasma were 11.9 and 22.6 mg/L, respectively, with elimination t1/2 values of ∼14 and 21 min. The peptide concentrations in blood remained above their MICs for 20 min for Onc72 and 80 min for Onc112. The highest peptide concentrations were detected in kidney homogenates, which also contained the highest content of metabolites, indicating, together with the results from analysis of urine samples, that both peptides are cleared through the kidneys. CONCLUSIONS: Onc72 and Onc112 reach organs, including the brain, within 10 min after intravenous and intraperitoneal administration. Onc112 remained in blood at concentrations above its MIC for 80 min. The pharmacokinetic profiles explain the high in vivo efficacies in models of systemic infection and indicate the potential use of these agents for the treatment of urinary tract infections.
OBJECTIVES: To evaluate the efficacy of antimicrobial peptide Onc112 in a lethal Escherichia coli infection model and the pharmacokinetics of Onc72 and Onc112 administered intravenously or intraperitoneally in mice. METHODS: Onc72, Onc112 and their major metabolites in blood, kidneys, liver, brain and urine were quantified by MS using multiple reaction monitoring (MRM) and isotope-labelled peptides. RESULTS: Onc112 rescued all animals when administered intraperitoneally at a dose of 2.5 mg/kg and was thus slightly more efficient than Onc72. The MRM method provided limits of quantification in plasma, urine and kidney, liver and brain homogenates of 7-80 μg/L, well below the MICs of 2-4 mg/L. Onc72 and Onc112 reached all organs within 10 min when administered intraperitoneally (5 mg/kg). Their initial concentrations in plasma were 11.9 and 22.6 mg/L, respectively, with elimination t1/2 values of ∼14 and 21 min. The peptide concentrations in blood remained above their MICs for 20 min for Onc72 and 80 min for Onc112. The highest peptide concentrations were detected in kidney homogenates, which also contained the highest content of metabolites, indicating, together with the results from analysis of urine samples, that both peptides are cleared through the kidneys. CONCLUSIONS: Onc72 and Onc112 reach organs, including the brain, within 10 min after intravenous and intraperitoneal administration. Onc112 remained in blood at concentrations above its MIC for 80 min. The pharmacokinetic profiles explain the high in vivo efficacies in models of systemic infection and indicate the potential use of these agents for the treatment of urinary tract infections.
Authors: Pavel M Kopeikin; Maria S Zharkova; Alexander A Kolobov; Maria P Smirnova; Maria S Sukhareva; Ekaterina S Umnyakova; Vladimir N Kokryakov; Dmitriy S Orlov; Boris L Milman; Sergey V Balandin; Pavel V Panteleev; Tatiana V Ovchinnikova; Aleksey S Komlev; Alessandro Tossi; Olga V Shamova Journal: Front Cell Infect Microbiol Date: 2020-10-19 Impact factor: 5.293
Authors: Laszlo Otvos; Eszter Ostorhazi; Dora Szabo; Steven D Zumbrun; Lynda L Miller; Stephanie A Halasohoris; Puvi D Desai; Sharon M Int Veldt; Carl N Kraus Journal: Front Chem Date: 2018-08-14 Impact factor: 5.221