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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
Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria.
Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
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2015 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 6, 1377Article in journal (Refereed) Published
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Text
Abstract [en]

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.

Place, publisher, year, edition, pages
Frontiers Media , 2015. Vol. 6, 1377
Keyword [en]
gonorrhea, treatment, antimicrobial resistance, time-kill curve analysis, pharmacodynamics, DNA topoisomerase II inhibitor, ETX0914
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Microbiology
Identifiers
URN: urn:nbn:se:oru:diva-47356DOI: 10.3389/fmicb.2015.01377ISI: 000366706900001PubMedID: 26696986OAI: oai:DiVA.org:oru-47356DiVA: diva2:891906
Note

Funding Agencies:

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) - SwissTransMed (Platforms for Translational Research in Medicine)

Örebro County Council Research Committee

Foundation for Medical Research at Örebro University Hospital, Sweden

Available from: 2016-01-08 Created: 2016-01-08 Last updated: 2016-01-08Bibliographically approved

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Jacobsson, SusanneUnemo, Magnus
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CiteExportLink to record
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