Integrated Omics-Based Discovery of Bioactive Halogenated Metabolites from the Deep-Sea Streptomyces sp. B188M101

Using the one-strain-many-compounds (OSMAC) culturing approach, metabolomic studies, and bioassay-guided purification, we have isolated and characterised three new chlorinated natural products, agelolines B-D (<b>1</b>-<b>3</b>), together with two known compounds, ageloline A (<b>4</b>) and gausemycin A (<b>5</b>), which have been identified by high-resolution mass spectrometry and 1D and 2D NMR analyses. The preliminary evaluation of three small-scale extracts (M400, R358 and SGG) against the fish pathogen, <i>Aeromonas salmonicida</i> subsp. <i>achromogenes</i> KELDUR265-87, showed that the R358 extract displayed significant activity. Furthermore, the natural products (<b>1</b>-<b>5</b>) were evaluated against the fish pathogen <i>Aeromonas salmonicida</i> and human pathogens (<i>Stenotrophomonas maltophilia</i> L2125, <i>Staphylococcus aureus</i> ATCC6538P, and <i>S. pneumoniae</i> L44) using a serial dilution assay. Compound <b>3</b> displayed activity against <i>Staphylococcus aureus</i> ATCC6538P, <i>S. maltophilia</i> L2125, and <i>S. pneumoniae</i> L44 with MIC values of 6, 32, and 64 µg/mL, respectively. Interestingly, only gausemycin A (<b>5</b>) exhibited considerable inhibition against <i>A. salmonicida</i> with an MIC value of 32 µg/mL, and the activity increased by two-fold when supplemented with 0.45 mM calcium salt, while <b>2</b> and <b>4</b> showed moderate inhibition against <i>S. maltophilia</i> L2125. The biosynthetic pathways of compounds <b>1</b>-<b>4</b> were proposed. This is the first report of specific inhibition of <i>A. salmonicida</i> by <b>5</b>.