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Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae

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Last modified
  • 02/20/2025
Type of Material
Authors
    Sunniva Foerster, University of BernDaniel Golparian, Örebro UniversitySusanne Jacobsson, Örebro UniversityLucy J. Hathaway, University of BernNicola Low, University of BernWilliam Shafer, Emory UniversityChristian L. Althaus, University of BernMagnus Unemo, Örebro University
Language
  • English
Date
  • 2015-12-10
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © 2015 Foerster, Golparian, Jacobsson, Hathaway, Low, Shafer, Althaus and Unemo.
License
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1664-302X
Volume
  • 6
Issue
  • DEC
Start Page
  • 1377
End Page
  • 1377
Grant/Funding Information
  • The present study was funded by an Interdisciplinary Ph.D. (IPh.D.) project grant from SystemsX.ch (The Swiss Initiative for Systems Biology), RaDAR-Go (Rapid Diagnosis of Antibiotic Resistance in Gonorrhoea) financed by SwissTransMed (Platforms for Translational Research in Medicine), the Örebro County Council Research Committee, and the Foundation for Medical Research at Örebro University Hospital, Sweden.
Supplemental Material (URL)
Abstract
  • Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.
Author Notes
Keywords
Research Categories
  • Biology, Microbiology
  • Health Sciences, Pharmacology

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