Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Antimicrob Agents Chemother. 2020 Jun 23;64(7). doi: 10.1128/AAC.02206-19.
The rise of extensively drug-resistant and multidrug-resistant strains of has occurred in parallel with the increasing demand for new drugs. However, the current methods of drug discovery are burdened with rigorous assessments and require more time than can be spared until gonococcal infections become difficult to control. To address this urgency, we utilized a drug-repurposing strategy and identified three clinically approved anthranilic acid drugs (tolfenamic acid, flufenamic acid, and meclofenamic acid) with potent antigonococcal activity, inhibiting 50% of the strains (MIC) from 4 to 16 μg/ml. Furthermore, tolfenamic acid showed indifferent activity with antibiotics of choice for gonococcal infections, azithromycin and ceftriaxone, in checkerboard assays with a fractional inhibitory concentration index ranging from 0.75 to 1.5. Fenamic acids reduced a high inoculum of below the limit of detection within 12 h and exhibited a low frequency of resistance. Interestingly, the fenamic acids did not inhibit the growth of commensal spp. that comprise the healthy female genital microbiota. Fenamic acids were also superior to ceftriaxone in reducing the burden of intracellular within infected endocervical cells by 99%. Furthermore, all three fenamic acids significantly reduced the expression of proinflammatory cytokines by infected endocervical cells. Finally, fenamic acids and other structurally related anthranilic acid derivatives were evaluated to ascertain a more in-depth structure-activity relationship (SAR) that revealed -phenylanthranilic acid as a novel antigonorrheal scaffold. This SAR study will pave the road to repositioning more potent fenamic acids analogues against .
随着对新药需求的增加，广泛耐药和多重耐药的 菌株也随之出现。然而，目前的药物发现方法受到严格评估的限制，需要更多的时间，而不能等到淋球菌感染难以控制时再去寻找药物。为了解决这一紧迫性，我们利用药物再利用策略，鉴定出三种具有强大抗淋球菌活性的临床批准的邻氨基苯甲酸类药物（甲苯酰胺酸、氟芬那酸和甲氯芬那酸），抑制了 50%的菌株（MIC），浓度范围为 4 至 16μg/ml。此外，甲苯酰胺酸在棋盘试验中与淋病感染的首选抗生素阿奇霉素和头孢曲松的活性差异不大，其部分抑菌浓度指数（FICI）范围为 0.75 至 1.5。邻氨基苯甲酸类药物可在 12 小时内将高浓度的 降低到检测限以下，且耐药频率较低。有趣的是，邻氨基苯甲酸类药物不会抑制构成健康女性生殖道微生物群的共生 种的生长。邻氨基苯甲酸类药物在降低感染的宫颈内细胞中 的细胞内负荷方面也优于头孢曲松，减少了 99%。此外，三种邻氨基苯甲酸类药物都显著降低了感染的宫颈内细胞中促炎细胞因子的表达。最后，评估了邻氨基苯甲酸类药物和其他结构相关的邻氨基苯甲酸衍生物，以确定更深入的结构-活性关系（SAR），揭示 -苯基邻氨基苯甲酸是一种新型抗淋病的支架。这项 SAR 研究将为重新定位更有效的邻氨基苯甲酸类药物治疗 铺平道路。
