β-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall

The prevalence of multidrug resistance has been increasingly witnessed during the past few decades. Resistance of human pathogenic fungi against the currently available antifungal agents has increased the frequency of fungal infections and associated mortality rates. The discovery of novel lead antifungal agents is important to challenge multidrug resistance. The present study examined the antifungal potential of chemically synthesized beta-Nitrostyrene derivatives. Among the eight beta-Nitrostyrene derivatives used in this study, SS45, SS46 and SS47 showed strong antifungal potential. The results show that beta-Nitrostyrene derivatives inhibited the growth of different species of human pathogenic Candida, particularly the highly prevalent C. albicans, C. glabrata and the emerging pathogenic C. auris species. Moreover, beta-Nitrostyrene derivatives also show strong antifungal activities against drug-resistant clinical isolates and drug transporter overexpressing fungal species. The drug susceptibility assays revealed that beta-Nitrostyrene derivatives are fungicidal and show the synergy of action when combined with antifungal drugs caspofungin and fluconazole. The transcriptomic study performed on C. albicans in the presence of beta-Nitrostyrene derivatives revealed the differential expression of genes related to cell wall metabolism. Mechanistically, beta-Nitrostyrene derivatives impact cell wall morphology, enhance ROS generation and modulate drug efflux. Collectively this study reveals that beta-Nitrostyrene derivatives have strong antifungal potential with a particular mode of activity similar to known cell wall perturbing antifungal agents and thus can be exploited as promising potential antifungal agents for further studies.

Automated summary

This study examined the antifungal potential of chemically synthesized beta-Nitrostyrene derivatives and found that they have strong inhibitory effects on pathogenic fungi and are effective against drug-resistant strains. Furthermore, the derivatives were found to impact cell wall morphology, enhance ROS generation, and modulate drug efflux.