Division of Infectious Diseases, Department of Internal Medicine, Stanford University, Stanford, CA, United States of America.
Department of Bioengineering, Stanford University, Stanford, CA, United States of America.
PLoS Negl Trop Dis. 2020 Mar 20;14(3):e0008150. doi: 10.1371/journal.pntd.0008150. eCollection 2020 Mar.
Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs.
寄生虫感染是人类痛苦、死亡和经济损失的主要原因，但由于将药物通过临床试验并推向市场所需的巨大成本，这些疾病的药物开发一直受到阻碍。鉴定对多种寄生虫病原体均有活性的单一化合物可以提高药物开发的经济激励，并简化治疗方案。我们最近对重用途化合物进行了针对原生动物寄生虫溶组织内阿米巴的筛选，该寄生虫是阿米巴痢疾的病原体，并发现了四种具有低微摩尔效力和类药性的化合物（放线菌酮、灵菌红素、奥巴他汀和尼替胺）。在这里，我们扩展了对这些药物的研究。我们检测了这些药物对溶组织内阿米巴滋养体的杀伤速度，发现这四种药物的作用速度都比目前的首选药物甲硝唑更快。我们进一步建立了一个多机构合作，以确定这些化合物是否对其他寄生虫和机会性病原体有效。我们发现放线菌酮、灵菌红素和奥巴他汀在体外均具有广谱抗寄生虫活性，包括对血吸虫、布氏锥虫和顶复门寄生虫的活性。在几种情况下，这些药物被发现比现有药物具有显著的改善。例如，奥巴他汀和灵菌红素在抑制血吸虫幼体方面都比目前的标准治疗药物吡喹酮更有效。此外，还观察到对致病性自由生活阿米巴（福氏耐格里阿米巴、曼氏利什曼原虫和棘阿米巴）具有低微摩尔效力，这些阿米巴会引起中枢神经系统感染，目前尚无可靠的治疗方法。这些结果，再加上这三种药物中的三种（奥巴他汀、放线菌酮和尼替胺）之前已经在人类中使用过，支持了这些化合物可以作为开发广谱抗寄生虫药物的基础的想法。
