| Summary: | Tuberculosis (TB) remains a public health crisis, requiring the urgent identification of new anti-mycobacterial drugs. We screened several organic and aqueous marine invertebrate extracts for their in vitro inhibitory activity against the causative organism, <i>Mycobacterium tuberculosis</i>. Here, we report the results obtained for 54 marine invertebrate extracts. The chemical components of two of the extracts were dereplicated, using <sup>1</sup>H NMR and HR-LCMS with GNPS molecular networking, and these extracts were further subjected to an activity-guided isolation process to purify the bioactive components. <i>Hyrtios reticulatus</i> yielded heteronemin <b>1</b> and <i>Jaspis splendens</i> was found to produce the bengamide class of compounds, of which bengamides P <b>2</b> and Q <b>3</b> were isolated, while a new derivative, bengamide S <b>5</b>, was putatively identified and its structure predicted, based on the similarity of its MS/MS fragmentation pattern to those of other bengamides. The isolated bioactive metabolites and semi-pure fractions exhibited <i>M. tuberculosis</i> growth inhibitory activity, in the range <0.24 to 62.50 µg/mL. This study establishes the bengamides as potent antitubercular compounds, with the first report of whole-cell antitubercular activity of bengamides P <b>2</b> and Q <b>3</b>.
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