Malaria remains a worldwide threat, afflicting over 200 million people each year. The emergence of drug resistance against existing therapeutics threatens to destabilize global efforts aimed at controlling Plasmodium spp. parasites, which is expected to leave vast portions of humanity unprotected against the disease. To address this need, systematic testing of a fungal natural product extract library assembled through the University of Oklahoma Citizen Science Soil Collection Program has generated an initial set of bioactive extracts that exhibit potent antiplasmodial activity (EC₅₀ < 0.30 μg/mL) and low levels of toxicity against human cells (less than 50% reduction in HepG2 growth at 25 μg/mL). Analysis of the two top-performing extracts from Trichoderma sp. and Hypocrea sp. isolates revealed both contained chemically diverse assemblages of putative peptaibol-like compounds that were responsible for their antiplasmodial actions. Purification and structure determination efforts yielded 30 new peptaibols and lipopeptaibols (1–14 and 28–43), along with 22 known metabolites (15–27 and 44–52). While several compounds displayed promising activity profiles, one of the new metabolites, harzianin NPDG I (14), stood out from the others due to its noteworthy potency (EC₅₀ = 0.10 μM against multi-drug-resistant P. falciparum line Dd2) and absence of gross toxicity toward HepG2 at the highest concentrations tested (HepG2 EC₅₀ > 25 μM, selectivity index > 250). The unique chemodiversity afforded by these fungal isolates serves to unlock new opportunities for translating peptaibols into a bioactive scaffold worthy of further development.

中文翻译：

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利用 Peptaibol 生物合成滥交进行下一代抗疟原虫治疗

疟疾仍然是全球性的威胁，每年折磨着 2 亿多人。针对现有疗法的耐药性的出现有可能破坏旨在控制疟原虫的全球努力。寄生虫，预计这将使大部分人类无法抵御这种疾病。为了满足这一需求，对通过俄克拉荷马大学公民科学土壤收集计划组装的真菌天然产物提取物库进行系统测试，产生了一组初始的生物活性提取物，这些提取物表现出强大的抗疟原虫活性（EC ₅₀ < 0.30 μg/mL）和低水平对人类细胞的毒性（在 25 μg/mL 时，HepG2 生长减少不到 50%）。两种表现最好的木霉提取物的分析sp. 和Hypocrea sp。分离株显示两者都含有化学上多样化的假定 peptaibol 样化合物组合，这些化合物负责它们的抗疟原虫作用。纯化和结构测定努力取得了30个新的peptaibols和lipopeptaibols（1 - 14和28 - 43），22种已知的代谢物（沿15 - 27和44 - 52）。虽然几种化合物显示出有希望的活性特征，但其中一种新代谢物 harzianin NPDG I ( 14 ) 由于其显着的效力（EC ₅₀ = 0.10 μM 对抗多重耐药性）而从其他化合物中脱颖而出恶性疟原虫系 Dd2) 并且在最高测试浓度下对 HepG2 没有总体毒性（HepG2 EC ₅₀ > 25 μM，选择性指数 > 250）。这些真菌分离物提供的独特化学多样性为将 peptaibols 转化为值得进一步开发的生物活性支架提供了新的机会。