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

A bioassay-guided chemical investigation of a bacterium, Streptomyces sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a ( 1 ) and A2a ( 2 ) as potent inhibitors of Dirofilaria immitis (heartworm) microfilaria (mf) motility (EC 50 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A ( 3 ) and the new N -methylated analog surugamide K ( 4 ). With biological data suggesting surugamides may also exhibit activity against D. immitis , 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, Streptomyces sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded 3 along with the new acyl-surugamides A1-A4 ( 5 - 8 ). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 ( 9 - 11 ), while derivatization of 3 returned the semi-synthetic surugamide S4 ( 12 ) and acyl-surugamides AS1-AS3 ( 13 - 15 ). The natural acyl-surugamide A3 ( 7 ) and semi-synthetic acyl-surugamide AS3 ( 15 ) were shown to selectively inhibit D. immitis mf motility (EC 50 3.3-3.4 µg/mL), however, unlike antimycins 1 and 2 , were inactive against the gastrointestinal nematode Haemonchus contortus L1-L3 larvae (EC 50 > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC 50 > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides 3 - 15 revealed that selective acylation of the Lys 3 -ε-NH 2 correlates with anthelmintic activity.