Along with azoles and echinocandines, Amphotericin B (AmB) is one of the drugs that are most commonly employed in the treatment of fungal infections. This polyene macrolide antibiotic is produced by Streptomyces nodosus and exhibits high therapeutic potency with very low resistance, a trait that has kept it on the market since early 60s.
A characteristic structural feature of polyene macrolide antibiotics, including AmB, is a closed amphipatic macrolide ring with multiple hydroxyl groups in the hydrophilic part of the molecule and an extended conjugated bond system in its hydrophobic part. Thanks to such chemical structure, AmB monomers are prone to both interaction with the lipid bilayer and formation of higher-order structures (oligomers), supposedly leading to the assembly of transmembrane channels - the postulated functional supramolecular structure that is responsible for the compound's biological activity. The therapeutical effect and selectivity of AmB result from its interaction with membrane sterols, present in both mammalian and fungal cells. The sterols, constituting up to 30% of eukaryotic lipid membranes (cholesterol in mammalian and ergosterol in fungal bilayers), are responsible for maintaining membrane fluidity and ordering of the hydrocarbon chains of lipid molecules. Notably, the formation of transmembrane channels has long been known to strictly depend on the presence of specific membrane sterols. In particular, in ergosterol-containing membranes the channels become more stable and allow for free efflux of cations; nevertheless, the difference in the effect of ergo- and cholesterol on channel stability is relatively minor, leading to cytotoxicity of AmB towards human cells.
Currently, there are no broadly efficient and non-toxic antifungal drugs on the market, and the ones used today suffer from a range of disadvantages (low solubility, poor fungicidal or only fungistatic activity, high nephro- or hepatotoxicity). AmB - a highly potent and broadly efficient fungicide - is no exception, as its therapeutic activity comes at the cost of high toxicity, creating an urgent need for new derivatives with enhanced antifungal activity and reduced toxicity.
The main goal of the project is to elucidate the exact mechanism of selective activity of AmB on the molecular level. The identification of the stage at which the drug interacts selectively with fungal membranes will allow to use AmB as a lead compound in designing new, less toxic derivatives, as well as will shed light on the general mechanisms of action of membrane-active agents. Eventually, the findings will allow to locate structural features whose modification shall enable the rational design of safe, highly active and selective antifungal antibiotics.
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