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

• Authors: Sunniva Foerster, University of Bern; Daniel Golparian, Örebro University; Susanne Jacobsson, Örebro University; Lucy J. Hathaway, University of Bern; Nicola Low, University of Bern; William Shafer, Emory University; Christian L. Althaus, University of Bern; Magnus Unemo, Örebro University
• Journal Title: Frontiers in Microbiology
• Volume: Volume 6, Number DEC
• Publisher: Frontiers Media | 2015-12-10, Pages 1377-1377
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fmicb.2015.01377
• Subjects: Biology, Microbiology; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; gonorrhea; treatment; antimicrobial resistance; time-kill curve analysis; pharmacodynamics; DNA topoisomerase II inhibitor; ETX0914; DNA GYRASE INHIBITOR; PHARYNGEAL GONORRHEA; ANTIMICROBIAL RESISTANCE; TREATMENT FAILURE; MULTIDRUG-RESISTANT; 500 MG; SPIROPYRIMIDINETRIONE AZD0914; UNTREATABLE GONORRHEA; CEFTRIAXONE; DRUG

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.