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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

Becker, Katja ; Cao, Sha ; Nilsson, Anna ; Erlandsson, Maria ; Hotop, Sven-Kevin ; Kuka, Janis ; Hansen, Jon ; Haldimann, Klara ; Grinberga, Solveiga ; Berruga-Fernández, Talia ; Huseby, Douglas L. ; Shariatgorji, Reza ; Lindmark, Evelina ; Platzack, Björn ; Böttger, Erik C. ; Crich, David ; Friberg, Lena E. ; Vingsbo Lundberg, Carina ; Hughes, Diarmaid ; Brönstrup, Mark ; Andrén, Per E. ; Liepinsh, Edgars ; Hobbie, Sven N.

EBioMedicine, 2021-11, Vol.73, p.103652-103652, Article 103652 [Periódico revisado por pares]

Netherlands: Elsevier B.V

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Título:
Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
Autor: Becker, Katja ; Cao, Sha ; Nilsson, Anna ; Erlandsson, Maria ; Hotop, Sven-Kevin ; Kuka, Janis ; Hansen, Jon ; Haldimann, Klara ; Grinberga, Solveiga ; Berruga-Fernández, Talia ; Huseby, Douglas L. ; Shariatgorji, Reza ; Lindmark, Evelina ; Platzack, Björn ; Böttger, Erik C. ; Crich, David ; Friberg, Lena E. ; Vingsbo Lundberg, Carina ; Hughes, Diarmaid ; Brönstrup, Mark ; Andrén, Per E. ; Liepinsh, Edgars ; Hobbie, Sven N.
Assuntos: acute pyelonephritis ; amikacin ; animal model ; animal tissue ; Animals ; Anti-bacterial agents ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - therapeutic use ; antibacterial activity ; antibiotic resistance ; antibiotic sensitivity ; apramycin ; Bacterial Infections - drug therapy ; Bacterial Infections - microbiology ; delta pH ; Disease Models, Animal ; Dose-Response Relationship, Drug ; drug efficacy ; Drug Resistance, Multiple, Bacterial - drug effects ; drug safety ; drug uptake ; efficacy ; Escherichia coli ; female ; gentamicin ; high performance liquid chromatography ; Humans ; Hydrogen-Ion Concentration ; in vitro study ; in vivo study ; kanamycin ; kidney function ; Klebsiella pneumoniae ; liquid chromatography-mass spectrometry ; male ; mass spectrometry ; Mice ; Microbial Sensitivity Tests ; minimum inhibitory concentration ; mouse ; multidrug resistance ; Nebramycin - analogs & derivatives ; Nebramycin - pharmacology ; Nebramycin - therapeutic use ; nephrotoxicity ; nonhuman ; permeability ; pharmacokinetics ; proton-motive force ; Pseudomonas aeruginosa ; Pyelonephritis - drug therapy ; Pyelonephritis - etiology ; rat ; Rats ; Research paper ; Treatment Outcome ; urinary tract ; urinary tract infection ; Urinary Tract Infections - drug therapy ; Urinary Tract Infections - etiology ; urine pH ; uropathogen
É parte de: EBioMedicine, 2021-11, Vol.73, p.103652-103652, Article 103652
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Descrição: 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). 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. 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. 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. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
Editor: Netherlands: Elsevier B.V
Idioma: Inglês

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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis

Netherlands: Elsevier B.V

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