Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
Katja Becker,
Sha Cao,
Anna Nilsson,
Maria Erlandsson,
Sven-Kevin Hotop,
Janis Kuka,
Jon Hansen,
Klara Haldimann,
Solveiga Grinberga,
Talia Berruga-Fernández,
Douglas L. Huseby,
Reza Shariatgorji,
Evelina Lindmark,
Björn Platzack,
Erik C. Böttger,
David Crich,
Lena E. Friberg,
Carina Vingsbo Lundberg,
Diarmaid Hughes,
Mark Brönstrup,
Per E. Andrén,
Edgars Liepinsh,
Sven N. Hobbie
Affiliations
Katja Becker
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland
Sha Cao
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden
Anna Nilsson
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, Box 591, 751 24 Uppsala, Sweden
Maria Erlandsson
RISE Research Institutes of Sweden, Forskargatan 20G, 151 36 Södertälje, Sweden
Sven-Kevin Hotop
Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany
Janis Kuka
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
Jon Hansen
Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen, Denmark
Klara Haldimann
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland
Solveiga Grinberga
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
Talia Berruga-Fernández
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden
Douglas L. Huseby
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden
Reza Shariatgorji
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, Box 591, 751 24 Uppsala, Sweden
Evelina Lindmark
RISE Research Institutes of Sweden, Forskargatan 20G, 151 36 Södertälje, Sweden
Björn Platzack
RISE Research Institutes of Sweden, Forskargatan 20G, 151 36 Södertälje, Sweden
Erik C. Böttger
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland
David Crich
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 W. Green Street, Athens, GA 30602, USA
Lena E. Friberg
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden
Carina Vingsbo Lundberg
Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen, Denmark
Diarmaid Hughes
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden
Mark Brönstrup
Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany
Per E. Andrén
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, Box 591, 751 24 Uppsala, Sweden
Edgars Liepinsh
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
Sven N. Hobbie
Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, CH-8006 Zurich, Switzerland; Corresponding author.
Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
