Inhibitory effect of novel Eugenol Tosylate Congeners on pathogenicity of Candida albicans

Shabir Ahmad Lone,Aijaz Ahmad

doi:10.1186/s12906-020-02929-0

Abstract

BackgroundThe 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.MethodsIn 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.ResultsETCs 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.ConclusionThe 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.

Highlights

The global prevalence of fungal diseases is increasing rapidly, which affects more than a billion people every year with significant mortality rate
We reported that eugenol tosylate congeners (ETCs) possess potent antifungal activity by inhibiting the ergosterol biosynthesis pathway in C. albicans [19]
ETCs inhibit Candida albicans adhesion Adhesion assay using the vital dye alamarBlue as the detection reagent was used to evaluate the effect of ETC-5, Table 2 List of primers used for Quantitative reverse transcription PCR (RT-qPCR) experiments

Summary

Introduction

The global prevalence of fungal diseases is increasing rapidly, which affects more than a billion people every year with significant mortality rate. 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. Candida species are the 2nd most common causative agents of fungal infections worldwide and ranked 5th among hospital-acquired pathogens [4, 5]. 90% of invasive fungal infections due to Candida species are mostly attributed to Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei and Candida parapsilosis [6]. Among these C. albicans remains the main causative agent [7]. The important virulence factors associated with C. albicans pathogenesis include adherence, morphogenesis, hydrolytic enzymes secretion and biofilm formation [10]

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Discussion

Conclusion