Department of Biological Sciences, Florida International University, Miami, FL, 33199, USA.
Antagen Pharmaceuticals, Canton, MA, 02021, USA.
Parasit Vectors. 2024 Sep 20;17(1):401. doi: 10.1186/s13071-024-06450-y.
Malaria is a mosquito-transmitted disease that kills more than half a million people annually. The lack of effective malaria vaccines and recently increasing malaria cases urge innovative approaches to prevent malaria. Previously, we reported that the extract from the soil-dwelling fungus Purpureocillium lilacinum, a common fungus from the soil, reduced Plasmodium falciparum oocysts in Anopheles gambiae midguts after mosquitoes contacted the treated surface before feeding.
We used liquid chromatography to fraction fungal crude extract and tract the active fraction using a contact-wise approach and standard membrane feeding assays. The purified small molecules were analyzed using precise mass spectrometry and tandem mass spectrometry.
We isolated four active small molecules from P. lilacinum and determined them as leucinostatin A, B, A2, and B2. Pre-exposure of mosquitoes via contact with very low-concentration leucinostatin A significantly reduced the number of oocysts. The half-maximal response or inhibition concentration (EC) via pre-exposure was 0.7 mg/m, similar to atovaquone but lower than other known antimalarials. The inhibitory effect of leucinostatin A against P. falciparum during intraerythrocytic development, gametogenesis, sporogonic development, and ookinete formation, with the exception of oocyst development, suggests that leucinostatins play a part during parasite invasion of new cells.
Leucinostatins, secondary metabolites from P. lilacinum disrupt malaria development, particular transmission to mosquitoes by contact. The contact-wise malaria control as a nonconventional approach is highly needed in malaria-endemic areas.
疟疾是一种由蚊子传播的疾病，每年导致超过 50 万人死亡。缺乏有效的疟疾疫苗和最近不断增加的疟疾病例，促使人们寻求创新方法来预防疟疾。此前，我们报道了从土壤中常见真菌——紫色拟青霉中提取的物质，能在蚊子接触处理过的表面后取食时减少冈比亚按蚊中肠内的疟原虫孢子。
我们使用液相色谱对真菌粗提取物进行分离，并采用接触式方法和标准膜喂养试验对活性成分进行追踪。使用精确质量质谱和串联质谱分析纯化的小分子。
我们从紫色拟青霉中分离出四种活性小分子，并将其确定为亮抑酶肽 A、B、A2 和 B2。通过接触预先暴露蚊子，可以显著减少孢子数量。半数最大反应或抑制浓度（EC）通过预先暴露为 0.7mg/m，与阿托伐醌相似，但低于其他已知的抗疟药物。亮抑酶肽 A 对疟原虫在红细胞内发育、配子发生、孢子生殖发育和动合子形成的抑制作用，除孢子发育外，表明亮抑酶肽在寄生虫入侵新细胞的过程中发挥作用。
亮抑酶肽是来自紫色拟青霉的次级代谢产物，可破坏疟原虫的发育，特别是通过接触传播给蚊子。在疟疾流行地区，需要采用这种非传统的接触式疟疾控制方法。
