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

Foerster, Sunniva; Golparian, Daniel; Jacobsson, Susanne; Hathaway, Lucy J; Low, Nicola; Shafer, William M; Althaus, Christian L; Unemo, Magnus (2015). Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae. Frontiers in Microbiology, 6, p. 1377. Frontiers 10.3389/fmicb.2015.01377

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Förster, Sunniva; Hathaway, Lucy Jane; Low, Nicola and Althaus, Christian

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services
500 Science > 570 Life sciences; biology

ISSN:

1664-302X

Publisher:

Frontiers

Language:

English

Submitter:

Doris Kopp Heim

Date Deposited:

19 Jan 2016 13:33

Last Modified:

11 Sep 2017 20:45

Publisher DOI:

10.3389/fmicb.2015.01377

PubMed ID:

26696986

Uncontrolled Keywords:

DNA topoisomerase II inhibitor; ETX0914; antimicrobial resistance; gonorrhea; pharmacodynamics; time-kill curve analysis; treatment

BORIS DOI:

10.7892/boris.75291

URI:

https://boris.unibe.ch/id/eprint/75291

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