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

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. How...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Anti-bacterial agents proton-motive force delta pH permeability drug uptake urinary tract Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/b25c8a267d4642389bf6d5a2908a5a98
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spelling	oai:doaj.org-article:b25c8a267d4642389bf6d5a2908a5a982021-11-04T04:32:37ZAntibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis2352-396410.1016/j.ebiom.2021.103652https://doaj.org/article/b25c8a267d4642389bf6d5a2908a5a982021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421004461https://doaj.org/toc/2352-3964Background: 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.Katja BeckerSha CaoAnna NilssonMaria ErlandssonSven-Kevin HotopJanis KukaJon HansenKlara HaldimannSolveiga GrinbergaTalia Berruga-FernándezDouglas L. HusebyReza ShariatgorjiEvelina LindmarkBjörn PlatzackErik C. BöttgerDavid CrichLena E. FribergCarina Vingsbo LundbergDiarmaid HughesMark BrönstrupPer E. AndrénEdgars LiepinshSven N. HobbieElsevierarticleAnti-bacterial agentsproton-motive forcedelta pHpermeabilitydrug uptakeurinary tractMedicineRMedicine (General)R5-920ENEBioMedicine, Vol 73, Iss , Pp 103652- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Anti-bacterial agents proton-motive force delta pH permeability drug uptake urinary tract Medicine R Medicine (General) R5-920
spellingShingle	Anti-bacterial agents proton-motive force delta pH permeability drug uptake urinary tract Medicine R Medicine (General) R5-920 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 Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
description	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.
format	article
author	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
author_facet	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
author_sort	Katja Becker
title	Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
title_short	Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
title_full	Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
title_fullStr	Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
title_full_unstemmed	Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
title_sort	antibacterial activity of apramycin at acidic ph warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/b25c8a267d4642389bf6d5a2908a5a98
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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

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