Targeting malaria parasites with novel derivatives of azithromycin.
Targeting malaria parasites with novel derivatives of azithromycin.
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DOI：
10.3389/fcimb.2022.1063407
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发表时间：
2022
影响因子：
5.7
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中科院分区：
文献类型：
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抗青蒿素恶性疟原虫寄生虫的传播是全球关注的问题，并突出表明需要为未来的治疗确定新的抗疟药物。阿奇霉素是一种临床上用于治疗疟疾的大环内酯类抗生素，通过两种机制杀死寄生虫：通过抑制顶质体的细菌样核糖体的“延迟死亡”，以及在整个血液阶段发育中快速杀死的“快速杀死”。在此，研究了22种阿奇霉素类似物对恶性疟原虫（最致命的人类疟疾）和诺氏疟原虫（一种经常感染人类的猴寄生虫）的延迟死亡和快速杀灭活性。17种类似物显示出对两种疟原虫的快速杀灭效果，在对恶性疟原虫和诺氏疟原虫治疗不到48或28小时后，其效力分别比阿奇霉素高出38至20倍。快速杀灭类似物在整个血液阶段生命周期中保持活性，包括恶性疟原虫寄生虫的环阶段（<12小时处理），并且对恶性疟原虫的选择性比人细胞高>5倍。异戊烯焦磷酸补充寄生虫，缺乏一个apicoplast同样敏感的快速杀死类似物，确认这些药物的快速杀伤活性是不针对apicoplast。此外，对含有寄生虫弓形虫和革兰氏阳性细菌肺炎链球菌的相关顶质体的活性没有显示出优于阿奇霉素的改善，突出了抗疟疾快速杀灭活性的特异性改善。寄生虫的代谢组学分析表明，最有效的化合物的非血红蛋白衍生肽的积累，这是类似于氯喹，同时也表现出积累的血红蛋白衍生肽，这是不存在的氯喹治疗。在这项研究中，阿奇霉素类似物的特点扩大了结构多样性，以前报道的快速杀死化合物，并提供了新的起点，开发阿奇霉素类似物与快速杀死抗疟活性。
The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the apicoplast, and ‘quick-killing’ that kills rapidly across the entire blood stage development. Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.