Fluorene derivatives as potent antifungal and antibiofilm agents against fluconazole-resistant Candida albicans

Abstract

Candida albicans ranks as one of the most common causes of fungal sepsis in hospitalized patients around the world with an increasing mortality rate. The current antifungal drugs in use face several limitations including fungal resistance due to biofilm formation. This has complicated the treatment landscape, necessitating the need for continued search for effective therapeutic options against drug-resistant C. albicans threats. Therefore, this study investigated eighteen fluorene derivatives for their antifungal and antibiofilm potential against C. albicans. Two fluorene derivatives namely: 9,9-bis(4-hydroxyphenyl) fluorene (BHPF) and fluorene-9-acetic acid (FAA) were identified as potential inhibitors of Candida biofilms, achieving 97 % and 89 % inhibition at 10 μg/mL. Microscopic studies also confirmed their antibiofilm efficacy, with BHPF demonstrating activities comparable to amphotericin B. Furthermore, BHPF inhibited planktonic cell growth at concentration as low as 5 μg/mL. Both BHPF and FAA exhibited fungicidal activity and also inhibited C. albicans virulence factors such as cell aggregation and hyphal formation. Notably, neither compound showed propensity for resistance development over 15 passages. Additionally, toxicity evaluations in both plant and Caenorhabditis elegans model revealed non-to mild toxicity, and the ADMET prediction also satisfied the criteria for drug-likeliness. The results of this multifaceted investigation highlight the potential of BHPF and FAA as novel antifungal agents targeting C. albicans infections and biofilm-related challenges.