Abstract | BACKGROUND: 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.
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Authors | 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 |
Journal | EBioMedicine
(EBioMedicine)
Vol. 73
Pg. 103652
(Nov 2021)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 34740109
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Anti-Bacterial Agents
- Nebramycin
- apramycin
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Topics |
- Animals
- Anti-Bacterial Agents
(pharmacology, therapeutic use)
- Bacterial Infections
(drug therapy, microbiology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Resistance, Multiple, Bacterial
(drug effects)
- Humans
- Hydrogen-Ion Concentration
- Mice
- Microbial Sensitivity Tests
- Nebramycin
(analogs & derivatives, pharmacology, therapeutic use)
- Pyelonephritis
(drug therapy, etiology)
- Rats
- Treatment Outcome
- Urinary Tract Infections
(drug therapy, etiology)
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