Foerster Sunniva, Golparian Daniel, Jacobsson Susanne, Hathaway Lucy J, Low Nicola, Shafer William M, Althaus Christian L, Unemo Magnus
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.
Front Microbiol. 2015 Dec 10;6:1377. doi: 10.3389/fmicb.2015.01377. eCollection 2015.
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.
淋病奈瑟菌对所有可用的治疗性抗菌药物均已出现耐药性，因此开发治疗淋病的新型有效药物至关重要。拓扑异构酶II抑制剂ETX0914（也称为AZD0914）是一种新型螺嘧啶三酮类抗菌药物，其作用机制与以往及目前所有淋病治疗药物均不同。在本研究中，进一步描述了淋病奈瑟菌对ETX0914的耐药决定因素，并通过一种新型体外时间杀菌曲线分析，检测了ETX0914对淋病奈瑟菌（ETX0914野生型、单步筛选的耐药突变体及外排泵突变体）生长的影响，以评估这种新型抗菌药物的药效学参数。为作比较，还分别检测了环丙沙星、阿奇霉素、头孢曲松和四环素（单独及与ETX0914联合使用时）。ETX0914对所有野生型菌株均具有快速杀菌作用，且药效学特性与环丙沙星相似。所有筛选出的耐药突变体在GyrB的氨基酸密码子D429或K450处均有突变，而MtrCDE外排泵失活可完全恢复对ETX0914的敏感性。单独使用ETX0914以及将其与阿奇霉素和头孢曲松联合使用时，对淋病奈瑟菌均高度有效，并且发现ETX0914与环丙沙星存在协同相互作用，尤其是对ETX0914耐药突变体。ETX0914单药治疗或与阿奇霉素联合使用（以覆盖其他性传播感染），应考虑用于III期临床试验及未来的淋病治疗。
