Abstract
Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with broad antimicrobial activities in the low µM range against Gram-positive and -negative bacteria, including antibiotic resistant strains, and fungi. Allicin reacts with thiol groups and can inactivate essential enzymes. However, allicin is unstable at room temperature and antimicrobial activity is lost within minutes upon heating to >80 °C. Allicin’s antimicrobial activity is due to the thiosulfinate group, so we synthesized a series of allicin analogues and tested their antimicrobial properties and thermal stability. Dimethyl-, diethyl-, diallyl-, dipropyl- and dibenzyl-thiosulfinates were synthesized and tested in vitro against bacteria and the model fungus Saccharomyces cerevisiae, human and plant cells in culture and Arabidopsis root growth. The more volatile compounds showed significant antimicrobial properties via the gas phase. A chemogenetic screen with selected yeast mutants showed that the mode of action of the analogues was similar to that of allicin and that the glutathione pool and glutathione metabolism were of central importance for resistance against them. Thiosulfinates differed in their effectivity against specific organisms and some were thermally more stable than allicin. These analogues could be suitable for applications in medicine and agriculture either singly or in combination with other antimicrobials.
Highlights
Garlic has been used since ancient times for its health beneficial properties and modern research has provided a scientific basis for this practice[1,2,3]
We showed that some of the thiosulfinates are active as a vapour and that as little as one hour exposure to allicin vapour was inhibitory to microbial growth
DBTS was immiscible with water, methanol and ethanol and decomposed in DMSO, but was found to be soluble and stable in dimethyl formamide (DMF), in which it was dissolved for use in experiments
Summary
Garlic has been used since ancient times for its health beneficial properties and modern research has provided a scientific basis for this practice[1,2,3]. Allicin reacts with low-molecular weight cellular thiols such as glutathione (GSH), shifting the GSH-based cellular redox-potential to a more oxidized state It was recently shown for Saccharomyces cerevisiae that treatment with allicin altered the ratio of reduced (GSH) and oxidized glutathione (GSSG) into a range that would predict induction of apoptosis and this was confirmed by cytological and genetic methods[37]. Allicin was shown to oxidize critical cysteines in Yap1p and Δyap[1] and Δglr[1] mutants were shown to be hypersensitive to allicin[38] This situation is analogous to the essential role of GSH in resistance of yeast to dipyridyl disulfide, which is a highly specific reagent for thiol groups, showing pronounced antifungal activity[39]
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