The genus Eremophila (family Scrophulariaceae) consists of approximately 200 species that are widely distributed in the semi-arid and arid regions of Australia. Multiple Eremophila spp. are used as traditional medicines by the First Australians in the areas in which they grow. They are used for their antibacterial, antifungal, antiviral, antioxidant, anti-diabetic, anti-inflammatory, and cardiac properties. Many species of this genus are beneficial against several diseases and ailments. The antibacterial properties of the genus have been relatively well studied, with several important compounds identified and their mechanisms studied. In particular, Eremophila spp. are rich in terpenoids, and the antimicrobial bioactivities of many of these compounds have already been confirmed. The therapeutic properties of Eremophila spp. preparations and purified compounds have received substantially less attention, and much study is required to validate the traditional uses and to highlight species that warrant further investigation as drug leads. The aim of this study is to review and summarise the research into the medicinal properties, therapeutic mechanisms, and phytochemistry of Eremophila spp., with the aim of focussing future studies into the therapeutic potential of this important genus.

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Serrulatane diterpenoids are natural products found in plants from a subset of genera within the figwort family (Scrophulariaceae). Many of these compounds have been characterized as having anti-microbial properties and share a common diterpene backbone. One example, leubethanol from Texas sage (Leucophyllum frutescens) has demonstrated activity against multi-drug-resistant tuberculosis. Leubethanol is the only serrulatane diterpenoid identified from this genus; however, a range of such compounds have been found throughout the closely related Eremophila genus. Despite their potential therapeutic relevance, the biosynthesis of serrulatane diterpenoids has not been previously reported. Here we leverage the simple product profile and high accumulation of leubethanol in the roots of L. frutescens and compare tissue-specific transcriptomes with existing data from Eremophila serrulata to decipher the biosynthesis of leubethanol. A short-chain cis-prenyl transferase (LfCPT1) first produces the rare diterpene precursor nerylneryl diphosphate, which is cyclized by an unusual plastidial terpene synthase (LfTPS1) into the characteristic serrulatane diterpene backbone. Final conversion to leubethanol is catalyzed by a cytochrome P450 (CYP71D616) of the CYP71 clan. This pathway documents the presence of a short-chain cis-prenyl diphosphate synthase, previously only found in Solanaceae, which is likely involved in the biosynthesis of other known diterpene backbones in Eremophila. LfTPS1 represents neofunctionalization of a compartment-switching terpene synthase accepting a novel substrate in the plastid. Biosynthetic access to leubethanol will enable pathway discovery to more complex serrulatane diterpenoids which share this common starting structure and provide a platform for the production and diversification of this class of promising anti-microbial therapeutics in heterologous systems.

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Background Eremophila R.Br. (Scrophulariaceae) is a diverse genus of plants with species distributed across semi-arid and arid Australia. It is an ecologically important genus that also holds cultural significance for many Indigenous Australians who traditionally use several species as sources of medicines. Structurally unusual diterpenoids, particularly serrulatane and viscidane-types, feature prominently in the chemical profile of many species and recent studies indicate that these compounds are responsible for much of the reported bioactivity. We have investigated the biosynthesis of diterpenoids in three species: Eremophila lucida, Eremophila drummondii and Eremophila denticulata subsp. trisulcata. Results In all studied species diterpenoids were localised to the leaf surface and associated with the occurrence of glandular trichomes. Trichome-enriched transcriptome databases were generated and mined for candidate terpene synthases (TPS). Four TPSs with diterpene biosynthesis activity were identified: ElTPS31 and ElTPS3 from E. lucida were found to produce (3Z,7Z,11Z)-cembratrien-15-ol and 5-hydroxyviscidane, respectively, and EdTPS22 and EdtTPS4, from E. drummondii and E. denticulata subsp. trisulcata, respectively, were found to produce 8,9-dihydroserrulat-14-ene which readily aromatized to serrulat-14-ene. In all cases, the identified TPSs used the cisoid substrate, nerylneryl diphosphate (NNPP), to form the observed products. Subsequently, cis-prenyl transferases (CPTs) capable of making NNPP were identified in each species. Conclusions We have elucidated two biosynthetic steps towards three of the major diterpene backbones found in this genus. Serrulatane and viscidane-type diterpenoids are promising candidates for new drug leads. The identification of an enzymatic route to their synthesis opens up the possibility of biotechnological production, making accessible a ready source of scaffolds for further modification and bioactivity testing.

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Background Worldwide, Streptococcus pyogenes is the leading cause of bacterial pharyngitis. To reduce the use of antibiotics, antimicrobial phytochemical-containing remedies, which have long been in use in traditional medicine, may provide new approaches for management of streptococcal pharyngitis. The objective of this study was to assess the inhibitory activities of 25 natural phenolic compounds against three strains of S. pyogenes. Methods After an initial screening, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the nine most effective phenolic compounds were determined. The effect of four compounds with the lowest MIC and MBC on streptococcal growth and biofilm formation was also studied. Results 1,2-Naphthoquinone and 5-hydroxy-1,4-naphthoquinone elicited the greatest anti-S. pyogenes activities with MICs ranging from 0.39 to 6.25 µg mL -1 and MBCs of 100 µg mL -1 . Both naphthoquinones inhibited the biofilm formation at concentrations ranging from 12.5 to 50 µg mL -1 . Biofilm reduction and altered bacterial cell structures were visible in scanning electron microscopy images of naphthoquinone-treated cells. Conclusion In conclusion, 1,2-naphthoquinone and 5-hydroxy-1,4-naphthoquinone inhibit S. pyogenes and should be further investigated as candidates for the management of streptococcal pharyngitis.

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We report a search for antimicrobial compounds in the Australian plant Eremophila serrulata. Bioassay directed fractionation of a diethyl ether extract prepared from the leaves of E. serrulata led to the isolation of two compounds, an omicron-naphthoquinone, 9-methyl-3-(4-methyl-3-pentenyl)-2,3-dihydronaphtho[1,8-bc]pyran-7,8-dione (2), and a serrulatane diterpenoid, 20-acetoxy-8-hydroxyserrulat-14-en-19-oic acid (3). Two other known serrulatane-type diterpenoids, 8,20-dihydroxyserrulat-14-en-19-oic acid (4) and 8,20-diacetoxyserrulat-14-en-19-oic acid (5) were also isolated. None of these compounds had previously been tested for antimicrobial activity. Compounds 2-5 showed antimicrobial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentrations (MICs) ranging from 15.6 to 250mug/mL. Compound 2 was the most active with an MIC of 15.6mug/mL and a minimum bactericidal concentration (MBC) of 125mug/mL. This compound also showed antimicrobial activity against other Gram-positive bacteria including Streptococcus pyogenes, and Streptococcus pneumoniae. No activity was observed for this compound against all Gram-negative bacteria tested.

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