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Published on: September 16, 2022
The sphingolipid inhibitor myriocin increases Candida auris susceptibility to amphotericin B
Hanna Stieber1, Lara Junghanns1, Hannah Wilhelm1
1Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany.
Background:
The emergence of the pathogenic yeast Candida auris is of global concern due to its ability to cause hospital outbreaks and develop resistance against all antifungal drug classes. Based on published data for baker's yeast Saccharomyces cerevisiae, sphingolipid biosynthesis, which is essential for maintaining membrane fluidity and formation of lipid rafts, could offer a target for additive treatment.
Methods:
We analysed the susceptibility of C. auris to myriocin, which is an inhibitor of the de novo synthesis of sphingolipids in eukaryotic cells in comparison to other Candida species. In addition, we combined sublethal concentrations of myriocin with the antifungal drugs amphotericin B and fluconazole in E-tests. Consequently, the combinatory effects of myriocin and amphotericin B were examined in broth microdilution assays.
Results:
Myriocin-mediated inhibition of the sphingolipid biosynthesis affected the growth of C. auris. Sublethal myriocin concentrations increased fungal susceptibility to amphotericin B. Isolates which are phenotypically resistant (≥2 mg/L) to amphotericin B became susceptible in presence of myriocin. However, addition of myriocin had only limited effects onto the susceptibility of C. auris against fluconazole.
Conclusions:
Our results show that inhibition of de novo sphingolipid biosynthesis increases the susceptibility of C. auris to amphotericin B. This may potentially enhance antifungal treatment options fighting this often resistant yeast pathogen.
Insights
Inhibiting sphingolipid biosynthesis with myriocin enhances Candida auris susceptibility to amphotericin B. This combination therapy offers a promising strategy against this multidrug-resistant yeast.
Area of Science:
- Mycology
- Biochemistry
- Antimicrobial Resistance
Background:
- Emergence of *Candida auris* as a global health threat due to hospital outbreaks and antifungal resistance.
- Sphingolipid biosynthesis, crucial for membrane integrity, is a potential therapeutic target, drawing parallels with *Saccharomyces cerevisiae*.
- Need for novel treatment strategies against multidrug-resistant *Candida auris*.
Purpose of the Study:
- To investigate the efficacy of myriocin, a sphingolipid biosynthesis inhibitor, against *Candida auris*.
- To evaluate the synergistic effects of myriocin in combination with established antifungal drugs (amphotericin B and fluconazole).
Main Methods:
- Susceptibility testing of *C. auris* to myriocin compared to other *Candida* species.
- E-tests to assess combined effects of sublethal myriocin concentrations with amphotericin B and fluconazole.
- Broth microdilution assays to confirm combinatory effects of myriocin and amphotericin B.
Main Results:
- Myriocin effectively inhibited *C. auris* growth by targeting sphingolipid biosynthesis.
- Sublethal myriocin concentrations resensitized amphotericin B-resistant *C. auris* isolates to the drug.
- Myriocin demonstrated limited impact on *C. auris* susceptibility to fluconazole.
Conclusions:
- Inhibition of de novo sphingolipid biosynthesis significantly increases *C. auris* susceptibility to amphotericin B.
- This approach presents a potential strategy to overcome amphotericin B resistance in *C. auris* infections.
- Combination therapy involving sphingolipid biosynthesis inhibitors may expand therapeutic options for difficult-to-treat *C. auris* cases.
