Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
Antimicrob Agents Chemother. 2013 Oct;57(10):4699-706. doi: 10.1128/AAC.00722-13. Epub 2013 Jul 15.
The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clinical trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight(-1), twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.
新型硝咪唑吡喃类化合物（S）-PA-824 对结核分枝杆菌具有很强的体外和体内抗菌活性，目前正在进行结核病（TB）的 II 期临床试验。与（R）-PA-824 无活性的结核分枝杆菌相反，我们在这里报告，PA-824 的两种对映异构体对引起内脏利什曼病（VL）的利什曼原虫都具有强大的杀寄生虫活性。在利什曼原虫感染的巨噬细胞中，（R）-PA-824 的活性比（S）-PA-824 高 6 倍。两种去硝基类似物均无活性，这突出表明硝基在作用机制中的重要性。尽管两种对映异构体的体外和体内药理学特征相似，但（R）-PA-824 在 VL 的小鼠模型中更有效，当以 100mgkg 体重（-1）的剂量每天口服给药两次，连续 5 天，可抑制 99%以上的寄生虫负荷。在结核分枝杆菌中，（S）-PA-824 是一种前药，被一种去氮黄素依赖的硝基还原酶（Ddn）激活，这种酶在利什曼原虫中不存在。与硝呋替莫和非达硝唑不同，过表达利什曼硝基还原酶的转基因寄生虫对（R）-PA-824 或（S）-PA-824 均不敏感，这表明该酶不是这些化合物的主要靶标。体外药物联合研究表明，非达硝唑和（R）-PA-824 具有相加作用，而（S）-PA-824 和（R）-PA-824 表现出轻微的拮抗作用。因此，（R）-PA-824 是 VL 晚期先导优化的有前途的候选药物，并且可能具有与非达硝唑联合治疗的潜力，后者目前正在进行 VL 的 II 期临床试验。
