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Inhibitory effect of novel Eugenol Tosylate Congeners on pathogenicity of Candida albicans
Shabir Ahmad Lone1, Aijaz Ahmad2,3
1Clinical Microbiology and Infectious Diseases, School of Pathology, Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa.
Background:
The global prevalence of fungal diseases is increasing rapidly, which affects more than a billion people every year with significant mortality rate. On the other hand, the development of new drugs to treat these fungal infections is slow, while the current antifungal therapy is insufficient and associated with adverse side effects and emerging multidrug resistance. Therefore, development of novel antifungal drugs with least or no toxicity and multi-target mechanisms of action is an immediate priority. Natural products have long been known to possess antimicrobial activities and are source of new drugs. Currently, modifying natural products to synthesize derivatives/analogues are of great scientific focus for discovering novel drugs with improved potency and safety. Modifications in eugenol to synthesize eugenol derivatives with enhanced antifungal activity have already been reported.
Methods:
In this study, three most active novel eugenol tosylate congeners (ETC-5, ETC-6 and ETC-7) were selected from our previous study to investigate their effect on major virulence factors of Candida albicans which include adherence, morphogenesis, hydrolytic enzymes secretion, biofilm formation and on expression of genes related to these virulence factors. Adherence and biofilm formation were studied by alamarBlue dye and XTT reduction assays respectively, hydrolytic enzyme secretion was evaluated by plate assays. Further, morphological transition was monitored microscopically and RT-qPCR was used to assess the gene expression levels.
Results:
ETCs significantly inhibited adherence in C. albicans with an inhibition range of 16-66%, and completely inhibited the morphogenesis at MIC values. Inhibition of proteinase and phospholipase activity was in the range of 2-48% and 8-34% respectively. Test compounds also significantly inhibit biofilm formation in C. albicans in the range of 7-77%. Furthermore, RT-qPCR results indicated a significant down regulation in expression levels of genes (ALS1, ALS2, ALS3, ALS9, CPH1, HWP1, SAP1, SAP2, SAP3 and PLB1) in C. albicans cells after treated with ETCs.
Conclusion:
The results indicated that these novel ETCs target major virulence factors of C. albicans and avert this commensal microbe to turn into pathogenic. However, further in-depth studies may facilitate the mechanisms involved by ETCs in targeting these virulence factors.
Insights
Novel eugenol tosylate congeners (ETCs) effectively inhibit key virulence factors in Candida albicans, including adherence, morphogenesis, and biofilm formation. These findings highlight ETCs as promising candidates for developing new antifungal therapies against emerging drug resistance.
Area of Science:
- Mycology
- Medicinal Chemistry
- Antimicrobial Drug Discovery
Background:
- Rising global fungal infections necessitate novel antifungal treatments due to current therapy limitations and resistance.
- Natural products and their derivatives, like eugenol derivatives, are crucial sources for developing new drugs with improved efficacy and safety.
- Eugenol tosylate congeners (ETCs) have shown potential in previous studies for enhanced antifungal activity.
Purpose of the Study:
- To investigate the impact of three novel eugenol tosylate congeners (ETC-5, ETC-6, ETC-7) on major virulence factors of Candida albicans.
- To evaluate the effects of ETCs on adherence, morphogenesis, hydrolytic enzyme secretion, and biofilm formation.
- To assess the influence of ETCs on the gene expression of virulence factors in Candida albicans.
Main Methods:
- Virulence factor assays including alamarBlue dye and XTT reduction for adherence and biofilm formation.
- Plate assays for evaluating hydrolytic enzyme secretion (proteinase and phospholipase).
- Microscopic monitoring of morphological transition and RT-qPCR for gene expression analysis.
Main Results:
- ETCs significantly inhibited adherence (16-66%) and completely inhibited morphogenesis at MIC values.
- Inhibition of proteinase (2-48%) and phospholipase (8-34%) activities was observed.
- Significant inhibition of biofilm formation (7-77%) and down-regulation of key virulence genes (e.g., ALS, SAP, HWP1, PLB1) were demonstrated.
Conclusions:
- Novel eugenol tosylate congeners effectively target major virulence factors of Candida albicans.
- ETCs demonstrate potential in preventing the transition of Candida albicans from commensal to pathogenic state.
- Further research is warranted to elucidate the precise mechanisms by which ETCs target these virulence factors.
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