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Biosensor-Enabled Discovery of CaERG6 Inhibitors and Their Antifungal Mode of Action against Candida albicans

Zhan Liu1,2, Yi Li1,2, Daijing Wei1,2

  • 1Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, 9 Section 4, Renmin Road South, Chengdu 610041, China.

ACS Infectious Diseases
|April 3, 2023
PubMed

Insights

A new antifungal compound, NP256, targets ergosterol biosynthesis in Candida albicans. This discovery offers a potential new treatment for dangerous fungal infections, alone or with existing drugs.

Area of Science:

  • Mycology
  • Biochemistry
  • Pharmacology

Background:

  • Opportunistic fungal infections, particularly by Candida albicans, pose significant public health risks due to high mortality rates and limited treatment options.
  • Ergosterol is a vital component of fungal cell membranes, making its biosynthesis pathway a key target for antifungal drug development.

Purpose of the Study:

  • To identify and characterize novel inhibitors of CaERG6, a critical enzyme in Candida albicans ergosterol biosynthesis, as potential antifungal agents.
  • To evaluate the efficacy of the identified inhibitor, NP256, in combating Candida albicans growth, biofilm formation, and morphological transition.

Main Methods:

  • Biosynthetic pathway comparison and functional characterization were used to identify CaERG6 as an antifungal target.
  • High-throughput screening employing a biosensor identified CaERG6 inhibitors from a small-molecule library.
  • The compound NP256 was further analyzed for its effects on ergosterol biosynthesis, gene expression, biofilm formation, and morphological transition in Candida albicans.

Main Results:

  • The CaERG6 inhibitor NP256 (palustrisoic acid E) was identified as a potential natural product antifungal.
  • NP256 effectively inhibits ergosterol biosynthesis, downregulates hyphal formation gene expression, blocks biofilm development, and disrupts morphological transition in Candida albicans.
  • NP256 significantly enhances the susceptibility of Candida albicans to existing antifungal medications.

Conclusions:

  • The CaERG6 inhibitor NP256 demonstrates significant potential as a novel antifungal compound.
  • NP256 can be utilized as a monotherapy or in combination with other antifungals to treat Candida albicans infections.
  • This research provides a promising new avenue for developing effective treatments against life-threatening fungal diseases.
Keywords:
Candida albicansantifungal agentbiofilmcombination drug therapyhigh-throughput screeningsterol 24-C-methyltransferase

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