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

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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BORIS DOI
10.7892/boris.75291
Date of Publication
December 10, 2015
Publication Type
Article
Division/Institute

Institut für Infektio...

Institut für Sozial- ...

Author
Förster, Sunniva Maritaorcid-logo
Institut für Sozial- und Präventivmedizin (ISPM)
Golparian, Daniel
Jacobsson, Susanne
Hathaway, Lucy Janeorcid-logo
Institut für Infektionskrankheiten
Low, Nicolaorcid-logo
Institut für Sozial- und Präventivmedizin (ISPM)
Shafer, William M
Althaus, Christianorcid-logo
Institut für Sozial- und Präventivmedizin (ISPM)
Unemo, Magnus
Subject(s)

600 - Technology::610...

300 - Social sciences...

500 - Science::570 - ...

Series
Frontiers in Microbiology
ISSN or ISBN (if monograph)
1664-302X
Publisher
Frontiers
Language
English
Publisher DOI
10.3389/fmicb.2015.01377
PubMed ID
26696986
Uncontrolled Keywords

DNA topoisomerase II ...

ETX0914

antimicrobial resista...

gonorrhea

pharmacodynamics

time-kill curve analy...

treatment

Description
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.
Handle
https://boris-portal.unibe.ch/handle/20.500.12422/137659
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FileFile TypeFormatSizeLicensePublisher/Copright statementContent
Foerster FrontMicrobiol 2015.pdftextAdobe PDF2.6 MBAttribution (CC BY 4.0)publishedOpen
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