Nordihydroguaiaretic acid (NDGA) exhibits potent anti-biofilm and antimicrobial activity against methicillin-resistant Staphylococcus aureus and Candida albicans

Abstract

Introduction

The global rise of antimicrobial resistance (AMR), particularly among biofilm-forming bacteria and fungi, has created an urgent need for novel therapeutics. Nordihydroguaiaretic acid (NDGA), a plant-derived polyphenolic lignan, has demonstrated promising biological activities, yet its potential as a dual-action antimicrobial agent remains underexplored.

Objectives

This study aimed to evaluate the antimicrobial and anti-biofilm activities of NDGA against methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans, elucidate its mechanism of action, and assess its in vivo efficacy and biosafety.

Materials and Methods

NDGA’s antimicrobial activities were assessed through MIC, time-kill, and biofilm disruption assays against standard and clinical isolates. Transcriptomic profiling and deep-learning–guided molecular docking were used to identify key microbial targets and regulatory pathways. In vivo efficacy was validated in Galleria mellonella and murine systemic infection models. Cytotoxicity, hemolysis, and acute toxicity assays were conducted to evaluate biosafety.

Results

NDGA exhibited potent antimicrobial activity, with MIC values of 32 μg/ml for S. aureus USA300 and 64 μg/ml for C. albicans SC5314. It effectively eradicated persister cells and disrupting mature biofilms of both MRSA and C. albicans. Transcriptomic analysis revealed that NDGA modulated multiple microbial virulence and biofilm-regulating pathways, including arginine biosynthesis in MRSA and ergosterol metabolism in C. albicans. Docking studies confirmed strong binding affinity of NDGA to critical microbial targets. In vivo, NDGA significantly improved survival rates, reduced pathogen burden, and alleviated tissue damage, showing comparable efficacy to vancomycin and fluconazole. NDGA demonstrated favorable biosafety with low cytotoxicity, minimal hemolysis, and no observable acute toxicity in mammalian models.

Conclusion

NDGA is a promising antimicrobial candidate capable of disrupting biofilms and overcoming drug resistance in both bacterial and fungal infections. Its multitargeted mode of action, coupled with in vivo efficacy and biosafety, supports further development as a next-generation anti-infective agent.