Adipostatins A–D from Streptomyces sp. 4875 inhibiting Brugia malayi asparaginyl-tRNA synthetase and killing adult Brugia malayi parasites

Lymphatic filariasis (LF), also known as elephantiasis, is one of the World Health Organization’s (WHO’s) top 10 neglected tropical diseases.¹ LF is caused primarily by two related parasites, Brugia malayi and Wuchereria bancrofti, and represents a worldwide health crisis with over 200 million people infected and another 20% of the global population at risk for infection.^{1, 2} Aminoacyl-tRNA synthetases (AARSs) were the first filarial targets for antiparasite drug discovery embraced by the WHO and are generally regarded as excellent therapeutic targets because AARSs have a key role in protein synthesis.³ Among the AARSs, in particular, asparaginyl-tRNA synthetase (AsnRS) in B. malayi is considered an excellent antifilarial target because (i) it is highly expressed in both sexes, adults and larvae of B. malayi; (ii) it is well characterized biochemically and structurally in B. malayi; (iii) it shows significant structural differences in comparison with human AARSs; and (iv) a high-throughput screening (HTS) platform with recombinant B. malayi AsnRS (BmAsnRS) for inhibitors has been developed.^{2, 4, 5, 6}

Natural products remain a valuable source of new drug leads and have demonstrated almost limitless potential in showcasing new molecular scaffolds with clinically relevant biological activities.⁷ In an effort to discover drug leads targeting BmAsnRS, we recently completed a HTS campaign of ~73 000 extracts from a collection of 36 720 microbial strains. Of the extracts screened, 177 active strains were identified. Subsequent bioassay-guided dereplication of two of the active strains resulted in the discovery of two natural product scaffolds as promising antifilarial drug leads, represented by tirandamycin B (TAM B) from Streptomyces sp. 17944⁸ and the depsipeptide WS9326D from Streptomyces sp. 9078.⁹ TAM B and WS9326D kill the adult B. malayi parasites at low nanomolar concentrations yet do not exhibit significant general cytotoxicity to human hepatic cells.^{8, 9}

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