A Novel Mechanistic Approach to Identify New Antifungal Lead Compounds Based on Amphotericin B Molecular Architecture

Purpose: To identify new antifungal lead compounds based on amphotericin B (AmB) molecular architecture. Methods: The strategy employed was molecular similarity search and screening based on the molecular constraints of polyene macrolide antibiotics, as well as docking experiments. Several new compounds were analyzed for their general inhibitory effect against indicator microbial strains. Interaction of the antifungal compounds with ergosterol and cholesterol was studied by UV-Vis spectroscopy and their effect on lipid/polydiacetylene (PDA) vesicles identified. Furthermore, the cytotoxicity of the compounds was evaluated and compared with that of amphotericin B. Results: In silico screening of 20,000 compounds obtained from the similarity search yielded seven candidates for in vitro antifungal test. The MIC of the more effective compounds, delta-decalactone and mandelonitrile, against three fungi - Candida albicans, Saccharomyces cerevisiae and spergillus niger - was in the range of 46.8 to 750.0 μg/ml. By comparing peak position shifts for the absorbance of mandelonitrile and delta-decalactone individually and in combination with sterols, it was found that mandelonitrile has a more selective interaction with ergosterol. The color change intensity of lipid/PDA vesicles indicated that delta-decalactone potently disturbed simulated memberane structure. Furthermore, cytotoxicity data for mandelonitrile and delta-decalactone on HepG2 and MCF7 show that mandelonitrile is less cytotoxic, with IC50 of 1095.04 and 2010.34 μg/ml, and more selective against fungal cells. Conclusion: This study presents a new insight into algorithmic discovery of novel antifungal agents by in silico methodology based on a mechanistic approach.