Increasing hydrophobicity of cyanobacterial puwainaphycins leads to lipopeptide variants with much improved therapeutic index

Cyclic lipopeptides from cyanobacteria represent an important class of compounds with antifungal properties. Their medical uses are frequently accompanied by cytotoxicity on host cells, so application as antifungal drugs is hampered [1]. In this study we demonstrate that natural lipopeptides known as puwainaphycins (sometimes called Minutissamides) isolated from Cylindrospermum alatosporum [2] with attached variable fatty acid (C10+n) chain length differ in the kinetics of their cytotoxic effect on human cells and their antifungal effect. Lipopeptides with an extended FA tail showed improved strain-specific antifungal activity against facultative pathogen Aspergillus fumigatus (MIC=0.5–3.8 µM) and plant pathogen Alternaria alternate (MIC=0.1–0.5 µM) but their cytotoxic effect was partially retained (~10 µM). Esterified at position 1’ lipopeptides possessed substantially higher antifungal potencies (MIC=0.2–0.6 µM against A. alternate) and greatly reduced (>20 µM) or abolished cytotoxic activity.

Publikationsverlauf

Artikel online veröffentlicht:
13. Dezember 2021

• References

• 1 Hrouzek P.. et al. Chemical Research in Toxicology 2012, 25(6), 1203–1211
• 2 Cheel J.. et al. Analytical and Bioanalytical Chemistry 2017, 409(4), 917–930