Siddiqui Ruqaiyyah, Mungroo Mohammad Ridwane, Anuar Tengku Shahrul, Alharbi Ahmad M, Alfahemi Hasan, Elmoselhi Adel B, Khan Naveed Ahmed
College of Arts and Sciences, American University of Sharjah, Sharjah 26666, United Arab Emirates.
Centre for Medical Laboratory Technology, Faculty of Health Sciences, Puncak Alam Campus, Universiti Teknologi MARA, Shah Alam 40450, Selangor, Malaysia.
Antibiotics (Basel). 2022 May 31;11(6):749. doi: 10.3390/antibiotics11060749.
Naegleria fowleri and Balamuthia mandrillaris are pathogenic free-living amoebae that infect the central nervous system with over 95% mortality rates. Although several compounds have shown promise in vitro but associated side effects and/or prolonged approval processes for clinical applications have led to limited success. To overcome this, drug repurposing of marketed compounds with known mechanism of action is considered a viable approach that has potential to expedite discovery and application of anti-amoebic compounds. In fact, many of the drugs currently employed in the treatment of N. fowleri and B. mandrillaris, such as amphotericin B, fluconazole, rifampin and miltefosine, are repurposed drugs. Here, we evaluated a range of clinical and laboratory compounds including metformin, quinclorac, indaziflam, inositol, nateglinide, 2,6-DNBT, trans-cinnamic acid, terbuthylazine, acarbose, glimepiride, vildagliptin, cellulase, thaxtomin A, repaglinide and dimethyl peptidase (IV) inhibitor against N. fowleri and B. mandrillaris. Anti-amoebic assays revealed that indaziflam, nateglinide, 2,6-DNBT, terbuthylazine, acarbose and glimepiride exhibited potent amoebicidal properties against both N. fowleri and B. mandrillaris. Notably, all compounds tested showed minimal human (HaCaT) cell cytotoxicity as determined by lactate dehydrogenase release. Prospective research using animal models is warranted to determine the potential of these repurposed compounds, as well as the need for investigating the intranasal route of delivery to treat these devastating infections.
福氏耐格里阿米巴和曼氏巴贝斯虫是致病性自由生活阿米巴，可感染中枢神经系统，死亡率超过95%。尽管几种化合物在体外已显示出前景，但相关的副作用和/或临床应用的漫长审批过程导致成效有限。为克服这一问题，对具有已知作用机制的上市化合物进行药物再利用被认为是一种可行的方法，有可能加快抗阿米巴化合物的发现和应用。事实上，目前用于治疗福氏耐格里阿米巴和曼氏巴贝斯虫的许多药物，如两性霉素B、氟康唑、利福平和米替福新，都是重新利用的药物。在此，我们评估了一系列临床和实验室化合物，包括二甲双胍、二氯喹啉酸、茚唑草酮、肌醇、那格列奈、2,6-二硝基苯并噻唑、反式肉桂酸、特丁津、阿卡波糖、格列美脲、维格列汀、纤维素酶、毒杀酚A、瑞格列奈和二肽基肽酶（IV）抑制剂对福氏耐格里阿米巴和曼氏巴贝斯虫的作用。抗阿米巴试验表明，茚唑草酮、那格列奈、2,6-二硝基苯并噻唑、特丁津、阿卡波糖和格列美脲对福氏耐格里阿米巴和曼氏巴贝斯虫均表现出强大的杀阿米巴特性。值得注意的是，通过乳酸脱氢酶释放测定，所有测试化合物对人（HaCaT）细胞的细胞毒性均最小。有必要使用动物模型进行前瞻性研究，以确定这些重新利用化合物的潜力，以及研究经鼻给药途径治疗这些毁灭性感染的必要性。
