New Cyclopeptides and Curvularins from Marine-Derived Fungal-Bacterial Symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532

Three new cyclic tetrapeptides (nectriatidels A-C, <b>1</b>-<b>3</b>), two new curvularin analogs (<b>6</b> and <b>7</b>), and four known compounds (<b>4</b> and <b>5</b>, <b>8</b> and <b>9</b>) were isolated from the marine-derived fungal-bacterial symbiont <i>Aspergillus spelaeus</i> GXIMD 04541/<i>Sphingomonas echinoides</i> GXIMD 04532, which was obtained from <i>Mauritia arabica</i> in shallow coastal waters. Their structures were elucidated through NMR spectroscopy and HRESIMS, and their absolute configurations were determined by Marfey's method and quantum chemical calculations. Compounds <b>1</b>-<b>5</b> showed moderate amphotericin B (AmB)-potentiating activity against <i>Candida albicans</i>. Compounds <b>7</b> and <b>8</b> exhibited significant activities against <i>Mycobacterium tuberculosis</i>, with MIC values of 32 and 16 μg/mL, respectively. Additionally, compounds <b>7</b> and <b>8</b> exhibited moderate cytotoxicity against human colorectal cancer cell lines DLD-1 and SW480, with IC₅₀ values of 25~36 μM. Whole-genome sequencing of <i>A. spelaeus</i> revealed a 35.91 Mb assembly encoding 106 biosynthetic gene clusters (BGCs). antiSMASH analysis revealed that 79 of these BGCs (74.5%) displayed no significant similarity to known pathways in the MIBiG database, which is dominated by hybrid clusters, terpene, T1PKS, NRPS, and NRPS-like types. Genomic analysis identified the putative biosynthetic gene clusters for these metabolites and confirmed the fungal host as the predominant producer.