Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritisShow others and affiliations
2021 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 73, article id 103652Article in journal (Refereed) Published
Abstract [en]
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)
Place, publisher, year, edition, pages
Elsevier B.V. , 2021. Vol. 73, article id 103652
Keywords [en]
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
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:ri:diva-56915DOI: 10.1016/j.ebiom.2021.103652Scopus ID: 2-s2.0-85118482945OAI: oai:DiVA.org:ri-56915DiVA, id: diva2:1613441
Note
Funding details: National Institutes of Health, NIH, HHSN272201700040I/HHSN27200001; Funding details: National Institute of Allergy and Infectious Diseases, NIAID; Funding details: University of Texas Medical Branch at Galveston, UTMB; Funding details: Seventh Framework Programme, FP7; Funding details: European Federation of Pharmaceutical Industries and Associations, EFPIA; Funding details: Stiftelsen för Strategisk Forskning, SSF, RIF14-0078; Funding details: Vetenskapsrådet, VR, 2018–05501; Funding details: Universität Zürich, UZH; Funding details: Science for Life Laboratory, SciLifeLab; Funding details: Innovative Medicines Initiative, IMI, 115583; Funding text 1: Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium (www.nd4bb-enable.eu) and has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement no. 115583 , resources of which are composed of financial contribution from the European Union's Seventh Framework Programme ( FP7/2007-2013 ) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The ENABLE project is also financially supported by contributions from Academic and Small and medium-sized enterprise (SME) partners.; Funding text 2: This work was further supported by the University of Zurich, Institute of Medical Microbiology.; Funding text 3: Some of the research leading to these results was conducted as part of the ND4BB European Gram-Negative Antibacterial Engine (ENABLE) Consortium (www.nd4bb-enable.eu) and has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement no. 115583, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and The European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The ENABLE project is also financially supported by contributions from Academic and Small and medium-sized enterprise (SME) partners. The University of Zurich has utilized the suite of preclinical services for in vivo assessment offered by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) (Contract No. HHSN272201700040I/HHSN27200001, with University of Texas Medical Branch at Galveston). This work was further supported by the Swedish Research Council (Grant number 2018?05501); the Swedish Foundation for Strategic Research [grant number RIF14-0078], and the Science for Life Laboratory to PEA. This work was further supported by the University of Zurich, Institute of Medical Microbiology.; Funding text 4: This work was further supported by the Swedish Research Council (Grant number 2018–05501 ); the Swedish Foundation for Strategic Research [grant number RIF14-0078 ], and the Science for Life Laboratory to PEA.
2021-11-222021-11-222021-11-22Bibliographically approved