Date of Award


Document Type


Degree Name

Philosophy (Ph.D)


Pharmaceutical Sciences

First Advisor

Blase C Billack

Second Advisor

Jerome Cantor

Third Advisor

Sandra Reznik


The current era is witnessing the emergence of virulent and resistant Candida and other pathogenic strains that has led to high morbidity and mortality rates on a global scale. Drug resistance has rendered once proven potent and commonly used antifungal drugs ineffective, especially in immunocompromised patients. These reasons justify the need for identifying novel antifungal targets and thereby building the antifungal armamentarium.

Our lab has previously investigated and studied Ebselen (EB), an organoselenium compound for its antifungal mechanism and activity against Candida strains. In vitro studies have shown the growth inhibitory activity (IC50 ˜ 15 µM) for various C. albicans strains. Furthermore, EB inhibits a novel fungal target H+-ATPase unlike the standard drugs available on the market. However, EB interacts with critical thiol residues of enzymes and exhibits numerous off-target effects. Also, EB is a poorly aqueous soluble drug and hence it is difficult to use for in vivo studies. For these reasons, the present study was carried out with two complementary strategies: Firstly, we have carried out an in vitro study intending to address the drug-resistance issue by building the antifungal library. Secondly, we molded EB into a topically acting nanoformulation for vulvovaginal candidiasis (VVC).

Given the current interest in organoselenium inhibitors of the plasma membrane H+ -ATPase, the first part of the study characterized the antifungal activity of forty novel organoselenium compounds (G1-G40) in S1 (fluconazole (FLU) sensitive) and S2 (FLU resistant) strains. Amongst the test compounds, G4, G13, G20 and G30 showed equivalent or better antifungal activity than EB in both the strains. Compound G20 was the most potent with a MIC of 3.125 µM in both strains while EB displayed a MIC of 25 µM and FLU-treated wells showed MIC >100 µM in both strains. In addition, medium acidification assays revealed that these selected EB analogs, indeed, act on the fungal membrane H+ -ATPase pump. Taken together, these in vitro results indicate that modified EB analogs should be investigated further for use as antifungal agents in FLU-resistant as well as other C. albicans strains.

Next, we developed a nanoformulation of EB (EBN) as an intervention to treat VVC, the most common infection caused by Candida albicans in women. EB loaded self-nanoemulsifying preconcentrate (EB-SNEP) was developed, characterized in vitro, and tested in a mouse model of VVC. In vivo studies carried out with intravaginal administration of EB-SNEP (12.5 mg/kg) showed a remarkable decrease in infection by ~ 800-fold compared to control (infected, untreated animals). In vitro studies of EBN formulation on mammalian cells and probiotic organisms and histological sections of EB-SNEP-treated mouse vaginal tissues did not demonstrate any signs of toxicity. To conclude, the present results indicate that EBN (12.5 mg/kg) should be investigated further for use as an antifungal agent in FLU-resistant as well as other Candida strains.

To recapitulate, organoselenium compounds proved to be effective and promising antifungal agents. Furthermore, EB nanoformulation provides a robust intravaginal delivery approach that overcomes issues related to poor-solubility drugs and simultaneously acting as a novel solution for drug-resistant strains.