Strevertene A, a Streptomyces-Derived Macrolide, Reveals Selective Activity against the Human Parasite <i>Schistosoma mansoni</i>

Schistosomiasis, a neglected tropical disease caused by parasitic blood flukes, affects 250 million humans worldwide, leading to widespread chronic illness and eventually death. Praziquantel is the only widely used and broadly effective drug for schistosomiasis; however, reports of reduced efficacy raise concerns about future therapy. To identify alternative compounds with antischistosomal activity, almost 1000 bacterial and fungal extracts were screened against adult Schistosoma mansoni worm pairs. This effort revealed Streptomyces sp. ST501019 is a producer of strevertene A, a 28-membered pentaene macrolide. Strevertene A caused detachment of adult worms, pair separation, and a minimum motility inhibition concentration of 14 μM. Most intriguingly, we observed potent in vitro activity against schistosomula (IC50 = 4 μM), a larval developmental stage of Schistosoma that is significantly less susceptible to praziquantel. Strevertene A exhibited a selectivity index (schistosomula activity over human cell toxicity) of more than 10 (HepG2 CC50 = 42 μM). Moreover, it showed no toxicity against Caenorhabditis elegans up to 110 μM. Genome sequencing of ST501019 identified a gene cluster for polyketide synthesis, which allowed us to derive a biosynthesis hypothesis of strevertenes. This study demonstrated for the first time the selective antischistosomula activity of strevertene A, identified through a microbial-natural-product-based screening approach against S. mansoni.