Australian Marine and Terrestrial -Derived Surugamides, and Synthetic Analogs, and Their Ability to Inhibit (Heartworm) Motility.

A bioassay-guided chemical investigation of a bacterium, sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a () and A2a () as potent inhibitors of (heartworm) microfilaria (mf) motility (EC 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A () and the new -methylated analog surugamide K (). With biological data suggesting surugamides may also exhibit activity against , a GNPS molecular network analysis of a library of microbes sourced from geographically diverse Australian ecosystems identified a further five taxonomically and chemically distinct surugamide producers. Scaled-up cultivation of one such producer, sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded along with the new acyl-surugamides A1-A4 (-). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 (-), while derivatization of returned the semi-synthetic surugamide S4 () and acyl-surugamides AS1-AS3 (-). The natural acyl-surugamide A3 () and semi-synthetic acyl-surugamide AS3 () were shown to selectively inhibit mf motility (EC 3.3-3.4 µg/mL), however, unlike antimycins and , were inactive against the gastrointestinal nematode L1-L3 larvae (EC > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides - revealed that selective acylation of the Lys-ε-NH correlates with anthelmintic activity.