Lynamicins H–P and Indimicin H: Chlorinated Bisindole Pyrroles from a Marine-Derived Streptomyces massiliensis and Their Biological Activities

High Resolution Image Download MS PowerPoint Slide Lynamicins H–P ( 1 – 4 and 6 – 10 ) and Indimicin H ( 5 ), ten previously unreported chlorinated bisindole pyrrole derivatives, along with five known lynamicins A–E ( 11 – 15 ), were isolated from the culture broth of the marine-derived actinomycete Streptomyces massiliensis 213DD-128 obtained from a sediment sample collected in the East Sea, Republic of Korea. The structures of 1 – 10 were elucidated by a comprehensive analysis of spectroscopic data, including NMR and HRESIMS. The absolute configurations of 5 and 7 – 9 were determined by comparison of their experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1 – 15 were assessed for their antimicrobial and cytotoxic activities. Notably, 10 exhibited approximately 7-fold stronger in vitro antibacterial activity (MIC = 0.5 μg/mL) than vancomycin (MIC = 3.8 μg/mL) against methicillin-resistant Staphylococcus aureus (MRSA) and also showed potent activity against pan-drug susceptible S. aureus (MIC = 0.4 μg/mL), and demonstrated pronounced in vitro cytotoxicity (GI 50 = 2.8–10.5 μM) against human cancer cell lines, except for the U266 cell line. Importantly, antibacterial efficacy was further supported in an ex vivo infection model, demonstrating activity beyond conventional in vitro assays. In contrast, 3 showed moderate antibacterial activity against MRSA (MIC = 2.3 μg/mL) compared with other compounds, while exhibiting weak or negligible cytotoxicity against normal human cell lines (MRC-9: GI 50 = 21.4 μM; RPMI-1788: GI 50 = >30 μM), highlighting its potential as a promising lead scaffold.