Treatment options for gonorrhoea are scarce. Drug repurposing of bioactive molecules approved for other conditions might therefore be of value. We developed a method for wide-scale, systematic drug repurposing screen to identify molecules with activity against Neisseria gonorrhoeae and screened the Prestwick Chemical Library (1200 FDA-approved drugs). As a proof-of-concept, we further examined one promising and interesting screening hit (auranofin; antirheumatic agent). Three WHO gonococcal reference strains (WHO F, O, P) were used for the Library screening. The strains were grown in presence of a fixed concentration of the library drugs in 384-well plates for 12 h, and the remaining bacterial respiration, to reflect growth, was then quantitatively measured using optical density (OD) 450 nm and a resazurin assay. The activity of auranofin was further examined using in vitro susceptibility testing (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)) against genetically diverse antimicrobial-resistant N. gonorrhoeae strains and time-kill assays. Sixty-eight molecules significantly inhibited bacterial growth of WHO F, O and P. Auranofin showed potent in vitro bactericidal activity (in MIC-, MBC- and time-kill assays) against four WHO reference strains. No cross-resistance between auranofin and any antimicrobial currently or previously used for gonorrhoea treatment was found when examining 51 selected antimicrobial-resistant gonococcal strains. In conclusion, this is the first wide-scale systematic screening effort for repurposing drugs for future treatment of gonorrhoea. Additional studies examining mechanism(s) of action, resistance development, in vivo anti-gonococcal activity and pharmacokinetics/pharmacodynamics for gonococcal infections of auranofin and several other significant screening hits would be valuable.

中文翻译：

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使用Prestwick化学文库（1200个生物活性分子）对淋病奈瑟氏球菌进行的首个大规模药物再利用筛选，鉴定了金诺芬和许多其他药物具有很高的体外活性。

淋病的治疗选择很少。因此，将药物用于其他条件的生物活性分子可能具有重要意义。我们开发了一种用于大规模，系统化药物再利用筛选的方法，以鉴定对淋病奈瑟菌具有活性的分子，并筛选了Prestwick化学文库（1200种FDA批准的药物）。作为概念验证，我们进一步检查了一种很有前途且有趣的筛选命题（金红霉素；抗风湿药）。文库筛选使用了三种WHO淋球菌参考菌株（WHO F，O，P）。使菌株在固定浓度的文库药物存在下于384孔板中生长12小时，然后使用光密度（OD）450 nm和刃天青测定法定量测量剩余细菌呼吸以反映生长。使用体外抗药性试验（最小抑菌浓度（MIC）和最小杀菌浓度（MBC））针对遗传多样性的耐药性淋病奈瑟氏球菌菌株和时间杀灭试验进一步检测金诺芬的活性。68个分子显着抑制WHO F，O和P的细菌生长。金诺芬对4种WHO参考菌株显示出有效的体外杀菌活性（在MIC，MBC和时间杀灭试验中）。检查选定的51种抗药性淋病球菌菌株时，金诺芬与目前或以前用于淋病治疗的任何抗菌剂之间均无交叉耐药性。总而言之，这是首次将药物用于将来的淋病治疗的大规模系统筛选工作。进一步研究行动机制，