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Pseudolaric Acid A: A Promising Antifungal Agent Against Prevalent Non-albicans Candida Species

Zhen Li1, Bin Zhu2, Weiqin Chen1

  • 1Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People's Republic of China.

Infection and Drug Resistance
|September 13, 2023
PubMed
Abstract

Insights

Pseudolaric acid A (PAA) shows antifungal activity against non-albicans Candida species. Combining PAA with fluconazole (FLC) demonstrates strong synergism, offering a potential new treatment for Candida infections.

Area of Science:

  • Mycology and Infectious Diseases
  • Pharmacology and Drug Discovery

Background:

  • Non-albicans Candida (NAC) species are increasingly implicated in bloodstream infections globally.
  • Emerging resistance to standard antifungal therapies necessitates the exploration of novel treatment strategies.
  • Pseudolaric acid A (PAA), a diterpenoid from Pseudolarix kaempferi, is investigated for its antifungal potential.

Purpose of the Study:

  • To evaluate the efficacy of Pseudolaric acid A (PAA) against key non-albicans Candida (NAC) species.
  • To determine the synergistic effect of PAA in combination with fluconazole (FLC) against NAC.
  • To elucidate the mechanisms underlying PAA's antifungal activity and its combination with FLC.

Main Methods:

  • Microdilution checkerboard and time-killing assays were employed to assess antifungal efficiency.
  • Cell wall and membrane integrity were examined using calcofluor white and propidium iodide staining.
  • Transmission electron microscopy (TEM) visualized ultrastructural changes, and XTT assay assessed viability with autophagy inhibition (3-MA).

Main Results:

  • PAA exhibited antifungal activity against *C. tropicalis, C. parapsilosis sensu stricto, C. orthopsilosis*, and *C. metapsilosis* (MIC 8-128 µg/mL).
  • Significant synergistic effects were observed when PAA was combined with FLC against FLC-resistant *C. tropicalis* (FICI 0.07-0.281).
  • PAA induced dose-dependent damage to *C. tropicalis* cell membranes, increased vacuole and autophagosome formation, and its effect was partially reversed by 3-MA.

Conclusions:

  • PAA demonstrates significant antifungal activity and synergistic potential with FLC against NAC species.
  • PAA's mechanism involves disruption of cell membranes and induction of autophagy in *C. tropicalis*.
  • The combination of PAA and FLC presents a promising therapeutic strategy for managing NAC infections.
Keywords:
antifungalautophagycombinationfluconazolenon-albicans Candidapseudolaric acid Asynergy

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