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Antibacterial activ...
Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
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- Becker, K. (author)
- University of Zurich, Switzerland,Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland
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- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Nilsson, Anna (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab
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- Erlandsson, Maria (author)
- RISE,Infrastruktur och betongbyggande,RISE Res Inst Sweden, Forskargatan 20G, S-15136 Södertälje, Sweden
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- Hotop, SK (author)
- Helmholtz Centre for Infection Research, Germany,Helmholtz Ctr Infect Res, Inhoffenstr 7, D-38124 Braunschweig, Germany
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- Kuka, J. (author)
- Latvian Institute of Organic Synthesis, Latvia,Latvian Inst Organ Synth, Aizkraukles 21, LV-1006 Riga, Latvia
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- Hansen, J. (author)
- Statens Serum Institute, Denmark,Statens Serum Inst, Artillerivej 5, DK-2300 Copenhagen, Denmark
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- Haldimann, K. (author)
- University of Zurich, Switzerland,Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland
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- Grinberga, S. (author)
- Latvian Institute of Organic Synthesis, Latvia,Latvian Inst Organ Synth, Aizkraukles 21, LV-1006 Riga, Latvia
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- Berruga Fernández, Talia (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Huseby, Douglas L (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Shariatgorji, Reza (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab
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- Lindmark, Evelina (author)
- RISE,Kemiska processer och läkemedel,RISE Res Inst Sweden, Forskargatan 20G, S-15136 Södertälje, Sweden
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- Platzack, Björn (author)
- RISE,Kemiska processer och läkemedel,RISE Res Inst Sweden, Forskargatan 20G, S-15136 Södertälje, Sweden
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- Böttger, E. C. (author)
- University of Zurich, Switzerland,Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland
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- Crich, D. (author)
- University of Georgia, USA,Univ Georgia, Dept Pharmaceut & Biomed Sci, 250 W Green St, Athens, GA 30602 USA
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- Friberg, Lena (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Vingsbo Lundberg, C. (author)
- Statens Serum Institute, Denmark,Statens Serum Inst, Artillerivej 5, DK-2300 Copenhagen, Denmark
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- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Institutionen för cell- och molekylärbiologi
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- Brönstrup, M. (author)
- Helmholtz Centre for Infection Research, Germany,Helmholtz Ctr Infect Res, Inhoffenstr 7, D-38124 Braunschweig, Germany
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- Andrén, Per E., Professor, 1957- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Liepinsh, E. (author)
- Latvian Institute of Organic Synthesis, Latvia,Latvian Inst Organ Synth, Aizkraukles 21, LV-1006 Riga, Latvia
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- Hobbie, S. N. (author)
- University of Zurich, Switzerland,Univ Zurich, Inst Med Microbiol, Gloriastr 30, CH-8006 Zurich, Switzerland
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(creator_code:org_t)
- Elsevier B.V. 2021
- 2021
- English.
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In: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Abstract
Subject headings
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- 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. © 2021 The Author(s)
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Anti-bacterial agents
- delta pH
- drug uptake
- efficacy
- nephrotoxicity
- permeability
- proton-motive force
- urinary tract
- amikacin
- apramycin
- gentamicin
- kanamycin
- acute pyelonephritis
- animal model
- animal tissue
- antibacterial activity
- antibiotic resistance
- antibiotic sensitivity
- Article
- drug efficacy
- drug safety
- Escherichia coli
- female
- high performance liquid chromatography
- in vitro study
- in vivo study
- kidney function
- Klebsiella pneumoniae
- liquid chromatography-mass spectrometry
- male
- mass spectrometry
- minimum inhibitory concentration
- mouse
- multidrug resistance
- nonhuman
- pH
- pharmacokinetics
- Pseudomonas aeruginosa
- rat
- urinary tract infection
- urine pH
- uropathogen
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Becker, K.
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Cao, Sha
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Nilsson, Anna
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Erlandsson, Mari ...
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Hotop, SK
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Kuka, J.
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show more...
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Hansen, J.
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Haldimann, K.
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Grinberga, S.
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Berruga Fernánde ...
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Huseby, Douglas ...
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Shariatgorji, Re ...
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Lindmark, Evelin ...
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Platzack, Björn
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Böttger, E. C.
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Crich, D.
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Friberg, Lena
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Vingsbo Lundberg ...
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Hughes, Diarmaid ...
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Brönstrup, M.
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Andrén, Per E., ...
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Liepinsh, E.
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Hobbie, S. N.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Infectious Medic ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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EBioMedicine
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RISE
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Uppsala University