Nammunige Nirupama A, Agnew-Francis Kylie A, Fernando Deepani D, Taylor Sara, Lu Hieng, Chow Sharon, Hartel Gunter, Okano Satomi, Williams Craig M, Fischer Katja
Scabies Laboratory, Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Veterinary Science, the University of Queensland, Brisbane, QLD, Australia.
School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, QLD, Australia.
Phytomedicine. 2025 Jan;136:156321. doi: 10.1016/j.phymed.2024.156321. Epub 2024 Dec 16.
Scabies is a debilitating and neglected infectious disease with limited effective treatment options and affecting millions of people worldwide, mainly in poor and overcrowded settings. Essential oils from Australasian Myrtaceae are known to have parasiticidal properties, often attributed to the presence of β-triketones, which are known inhibitors of the tyrosine catabolism pathway through inhibition of hydroxyphenylpyruvate dioxygenase (HPPD).
In this study, essential oils from mānuka (Leptospermum scoparium) were evaluated in vitro for miticidal and ovicidal activities and their active β-triketone constituents (flavesone, leptospermone, and isoleptospermone) were identified.
Mite survival and egg hatching bioassays were performed to assess the scabicidal (miticidal and ovicidal) properties of Australasian Myrtaceae essential oils (mānuka, tea tree, and kunzea), mānuka oil fractions and three β-triketones (leptospermone, isoleptospermone, flavesone). Scabicidal constituents of mānuka oil were determined and quantified by H NMR spectroscopy and gas chromatography. To investigate HPPD as a potential target of β-triketones in scabies, tyrosine and fumarate levels were measured in mites following exposure to flavesone, and in silico docking of β-triketones in homology models of scabies HPPD structures was performed.
Mānuka oil had superior scabicidal activity compared to conventional treatments, ivermectin and permethrin, as well as kunzea and tea tree oils. The analysis of the chemical composition of mānuka oil revealed a high abundance of sesquiterpenes (42 %), and three β-triketones, flavesone (4.7 %), leptospermone (17.2 %), and isoleptospermone (5.1 %). Miticidal and ovicidal activity was strongly correlated with the presence of these β-triketones, but not the sesquiterpenes. The β-triketones had similar miticidal activity (LC50 58.6-61.7 mM at 4 h; LT50 1.3-1.4 h at 150 mM) to each other and to mānuka oil, and showed high ovicidal activity in young and mature eggs, with leptospermone being the most potent (LC50 33.6-75.9 mM). Significantly altered tyrosine and fumarate levels in mites after exposure to flavesone compared to untreated mites indicate a possible interference of flavesone with the tyrosine catabolism pathway. Molecular docking experiments indicate that this activity is likely underpinned by their inhibition of the Sarcoptes scabiei hydroxyphenylpyruvate dioxygenase (SsHPPD).
Our results demonstrated that mānuka oil and the β-triketones flavesone, leptospermone, and isoleptospermone can effectively kill scabies mites and eggs at early and late developmental stages, likely through their inhibition of tyrosine catabolism. This work has revealed SsHPPD as a potential new target for the development of novel topical scabies drugs that target all life-stages of the parasite.
疥疮是一种使人衰弱且被忽视的传染病，有效治疗选择有限，全球数百万人受其影响，主要集中在贫困和拥挤的环境中。已知澳大拉西亚桃金娘科植物的精油具有杀寄生虫特性，这通常归因于β - 三酮的存在，β - 三酮是通过抑制对羟基苯丙酮酸双加氧酶（HPPD）来抑制酪氨酸分解代谢途径的已知抑制剂。
在本研究中，对麦卢卡（Leptospermum scoparium）精油进行体外杀螨和杀卵活性评估，并鉴定其活性β - 三酮成分（黄烷酮、细籽酮和异细籽酮）。
进行螨虫存活和卵孵化生物测定，以评估澳大拉西亚桃金娘科植物精油（麦卢卡、茶树和昆士亚）、麦卢卡油馏分以及三种β - 三酮（细籽酮、异细籽酮、黄烷酮）的杀疥（杀螨和杀卵）特性。通过核磁共振氢谱和气相色谱法测定并定量麦卢卡油的杀疥成分。为研究HPPD作为疥疮中β - 三酮的潜在靶点，在螨虫暴露于黄烷酮后测量酪氨酸和富马酸水平，并对β - 三酮在疥疮HPPD结构同源模型中进行分子对接。
与传统治疗药物伊维菌素和氯菊酯以及昆士亚油和茶树油相比，麦卢卡油具有更强的杀疥活性。麦卢卡油化学成分分析显示倍半萜含量高（42%），以及三种β - 三酮，黄烷酮（4.7%）、细籽酮（17.2%）和异细籽酮（5.1%）。杀螨和杀卵活性与这些β - 三酮的存在密切相关，与倍半萜无关。β - 三酮彼此之间以及与麦卢卡油具有相似的杀螨活性（4小时时LC50为58.6 - 61.7 mM；150 mM时LT50为1.3 - 1.4小时），并且在幼卵和成熟卵中均显示出高杀卵活性，其中细籽酮活性最强（LC50为33.6 - 75.9 mM）。与未处理的螨虫相比，暴露于黄烷酮后的螨虫酪氨酸和富马酸水平发生显著变化，表明黄烷酮可能干扰酪氨酸分解代谢途径。分子对接实验表明，这种活性可能是由于它们对疥螨对羟基苯丙酮酸双加氧酶（SsHPPD）的抑制作用。
我们的结果表明，麦卢卡油以及β - 三酮黄烷酮、细籽酮和异细籽酮可有效杀死发育早期和晚期的疥疮螨虫和卵，可能是通过抑制酪氨酸分解代谢实现的。这项工作揭示了SsHPPD作为开发针对寄生虫所有生命阶段的新型局部疥疮药物的潜在新靶点。
