β-Triketones from Leptospermum scoparium (mānuka) oil show potential as scabicides

Background: 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).

Purpose: 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.

Methods: 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 ¹H 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.

Results: 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).

Conclusions: 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.