Molecular Umbrellas Modulate the Selective Toxicity of Polyene Macrolide Antifungals

Abstract

Antifungal polyene macrolide antibiotics Amphotericin B (AmB) and Nystatin (NYS) were conjugated through the ω-amino acid linkers with diwalled "molecular umbrellas" composed of spermidine-linked deoxycholic or cholic acids. The presence of "umbrella" substituents modulated biological properties of the antibiotics, especially their selective toxicity. Some of the AmB-umbrella conjugates demonstrated antifungal in vitro activity comparable to that of the mother antibiotic but diminished mammalian toxicity, especially the hemolytic activity. In contrast, antifungal in vitro activity of NYS-umbrella conjugates was strongly reduced and all these conjugates demonstrated poorer than NYS selective toxicity. No correlation between the aggregation state and hemolytic activity of the novel conjugates was found.

Searching for Conjugates as New Structures for Antifungal Therapies

“…The AmB conjugates showed comparable antifungal activity and reduced hemolytic activity relative to the parent drug. In contrast, in the case of NY, its conjugates showed reduced antifungal activity and increased toxicity . Meanwhile, the use of a molecular umbrella composed of O-sulfate residues of cholic acid in the synthesis of conjugates with cispentacin (CisP) containing the “trimethyl lock” (TML) or O-dithiobenzylcarbamoyl group resulted in obtaining antifungal compounds without hemolytic properties.…”

“… Skwarecki et al showed that conjugates containing a dihedral molecular umbrella can penetrate the cell wall in Candida cells. This allows further research to construct more active conjugates with molecules other than cispentacin. , …”

Molecular Umbrella as a Nanocarrier for Antifungals

“…Nevertheless, this linker has not been employed so far for the construction of antimicrobial umbrella conjugates. The esterase-triggered TML (‘trimethyl lock’) [ 15 ], applied originally in antibacterial siderophore conjugates [ 16 , 17 ], has been for the first time used for the construction of potential antifungal conjugates.…”

Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

“…The most well-known polyene, amphotericin B (AmB), is one of the most potent fungicidal agents on the market with a broad-spectrum of activity, shown to be effective against Cryptococcus spp. and most Candida spp., but several next generation drugs have been in the making [ 3 , 4 , 5 ]. (ii) Azoles are a class of antifungal drugs that target lanosterol-14α-demethylase (Erg11), which catalyzes the demethylation of lanosterol to make an important precursor that is eventually converted into ergosterol [ 6 , 7 ].…”