Oceanapiside, a Marine Natural Product, Targets the Sphingolipid Pathway of Fluconazole-Resistant <i>Candida glabrata</i>

• Main Authors: Doralyn S. Dalisay, Evan W. Rogers, Tadeusz F. Molinski
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Marine Drugs
• Subjects: antifungal; Porifera; azole; long-chain base; sphingolipid
• Online Access: https://www.mdpi.com/1660-3397/19/3/126

Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant <i>Candida glabrata</i> at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in <i>C. glabrata</i>, which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.