title: Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae.
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.
authors.affiliation: 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.
authors.forename: Sunniva
authors.initials: S
authors.lastname: Foerster
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Faculty of Medicine and Health, Örebro University Örebro, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Golparian
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Faculty of Medicine and Health, Örebro University Örebro, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jacobsson
authors.affiliation: Institute for Infectious Diseases, University of Bern Bern, Switzerland.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Hathaway
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern Bern, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Low
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta GA, USA ; Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur GA, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Shafer
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern Bern, Switzerland.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Althaus
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Faculty of Medicine and Health, Örebro University Örebro, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
keywords: DNA topoisomerase II inhibitor; ETX0914; antimicrobial resistance; gonorrhea; pharmacodynamics; time-kill curve analysis; treatment