Triterpenoids from <i>Ganoderma gibbosum</i>: A Class of Sensitizers of FLC-Resistant <i>Candida albicans</i> to Fluconazole

Abstract

Fungal drug resistance is a major health threat, and reports of clinical resistance worldwide are becoming increasingly common. In a research program to discover new molecules to help overcome this problem, 14 new lanostane-type triterpenoids, gibbosicolids A-G (<b>2</b>-<b>8</b>) and gibbosic acids I-O (<b>9</b>-<b>15</b>), were isolated from the fruiting bodies of <i>Ganoderma gibbosum</i>, along with seven known triterpenoid derivatives. These compounds featured high levels of oxidation, epimerization, and γ-lactonization. Structures were elucidated by comprehensive spectroscopic analyses and HRMS data. Absolute configurations were assigned based on quantum chemical calculations, including calculated chemical shift with DP4+ analysis, coupling constants, and electronic circular dichroism (ECD) methods. Results show that the calculated NMR with DP4+ analysis could not reliably establish the overall spatial configuration of molecules possessing independent and free-rotational stereoclusters. All these compounds significantly increased the sensitivity of fluconazole (FLC)-resistant <i>C. albicans</i> to FLC. Compounds <b>2</b>, <b>5</b>, <b>9</b>, <b>12</b>, <b>16</b>, <b>17</b>, and <b>21</b> exhibited strong antifungal activity against FLC-resistant <i>C. albicans</i> when combined with FLC, with MIC₅₀ values ranging from 3.8 to 8.8 μg/mL.