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Updated: Jun 4, 2025
Author Spotlight: Advancing Antimicrobial Resistance Research with Innovative Approaches and Synthetic Compounds
Published on: September 27, 2024
Design, Synthesis, and Anti-Infective Effect Against Candida Albicans of a New Urolithin Derivative
Chenyan Zhu1, Long Tang1, Feng Zhou1
1School of Pharmacy & School of Biological and Food Engineering, Changzhou University, Changzhou, China.
Abstract:
Deep mucosal and organ infections caused by the infestation of Candida albicans in immunocompromised patients represent a significant cause of mortality in hospitalized patients. The rise in fungal resistance is a consequence of the overuse of antibiotics. Therefore, innovative immunostimulants must be developed to combat pathogenic fungal infections. We used urolithin A (UA), an intestinal metabolite rich in the naturally occurring polyphenolic antioxidants ellagic acid (EA) or ellagitannin (ET), as a lead compound for structural modification. Through liquid screening of 17 synthesized compounds, we discovered compound 1e effectively inhibited C. albicans biofilm formation, thereby reducing its virulence. Furthermore, it protects animals from severe infections by enhancing tolerance to infection by intestinal pathogens and reducing oxidative stress. Moreover, our findings indicate that compound 1e exerts its effects through the p38 mitogen-activated protein kinase (MAPK) innate immune pathway, which is evolutionarily conserved. These observations not only enhance our comprehension of immune mechanisms but also provide a crucial foundation for the development of immune activators with the potential to resist pathogenic bacterial infections.
Insights
A novel compound derived from urolithin A effectively inhibits Candida albicans biofilm formation and enhances host defense against fungal infections by modulating the p38 MAPK pathway.
Area of Science:
- Microbiology
- Immunology
- Drug Discovery
Background:
- Deep mucosal and organ infections caused by Candida albicans are a major cause of mortality in immunocompromised patients.
- Increasing antifungal resistance, driven by antibiotic overuse, necessitates novel immunostimulants.
- Urolithin A (UA), a metabolite of ellagic acid/ellagitannin, serves as a lead compound for developing new therapeutic agents.
Purpose of the Study:
- To develop innovative immunostimulants to combat pathogenic fungal infections.
- To identify novel compounds that inhibit Candida albicans virulence and enhance host tolerance to infection.
- To elucidate the immune pathways targeted by these novel compounds.
Main Methods:
- Structural modification of urolithin A (UA) and synthesis of 17 compounds.
- Liquid screening of synthesized compounds for anti-Candida albicans activity.
- In vivo assessment of compound efficacy in animal models of infection, including evaluation of oxidative stress and immune pathway activation (p38 MAPK).
Main Results:
- Compound 1e demonstrated significant inhibition of Candida albicans biofilm formation, reducing fungal virulence.
- Compound 1e protected animals from severe infections, enhanced tolerance to intestinal pathogens, and reduced oxidative stress.
- Compound 1e's mechanism of action involves the p38 mitogen-activated protein kinase (MAPK) innate immune pathway.
Conclusions:
- Compound 1e is a promising lead for developing novel immune activators against pathogenic fungal infections.
- The findings deepen the understanding of innate immune mechanisms in combating Candida albicans.
- This research provides a foundation for developing therapies to resist pathogenic infections through immune modulation.
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