Discovery of Meroterpenoids with Antifungal Activity from Deep-Sea-Derived Fungus <i>Acremonium sclerotigenum</i> LW14

Thirteen previously unreported ascochlorin-type meroterpenoids, acrocholrins A-M (<b>1</b>-<b>13</b>), together with seven known analogues (<b>14</b>-<b>20</b>) were characterized from the deep-sea-derived fungus <i>Acremonium sclerotigenum</i> LW14 guided by LC-MS/MS-based molecular networking. Their structures and absolute configurations were determined unambiguously by spectroscopic analysis, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction experiments. Compounds <b>1</b>/<b>3</b>, <b>2</b>/<b>14</b>, <b>6</b>/<b>7</b>, <b>8</b>/<b>17</b>, and <b>15</b>/<b>16</b> are diastereomers isomerized at C-10. Additionally, compounds <b>5</b>, <b>11</b>, <b>12</b>, and <b>13</b> represent rare ascochlorin analogues featuring an uncommon 19<i>S</i> configuration in the cyclohexanone ring. Compounds <b>9</b>, <b>11</b>, and <b>19</b> exhibited antifungal activity against <i>Cryptococcus gattii</i> 3271G1 with the same minimum inhibitory concentration (MIC) of 4 μg/mL. Preliminary mechanistic studies showed that compound <b>9</b> exhibited its anti-<i>C. gattii</i> activity by inhibiting capsule formation and increasing cell membrane permeability.