Unraveling the structure–activity relationship of tomatidine, a steroid alkaloid with unique antibiotic properties against persistent forms of Staphylococcus aureus

•Tomatidine is bactericidal against small colony variant of Staphylococcus aureus.•Tomatidine potentiates aminoglycosides against normal strains of S. aureus.•The SAR indicates the closed form of the alkaloid is the active one.•The two extremities of the molecule are responsible for its biological activity.

Staphylococcus aureus (S. aureus) is responsible for difficult-to-treat and relapsing infections and constitutes one of the most problematic pathogens due to its multiple resistances to clinically available antibiotics. Additionally, the ability of S. aureus to develop small-colony variants is associated with a reduced susceptibility to aminoglycoside antibiotics and in vivo persistence. We have recently demonstrated that tomatidine, a steroid alkaloid isolated from tomato plants, possesses anti-virulence activity against normal strains of S. aureus as well as the ability to potentiate the effect of aminoglycoside antibiotics. In addition, tomatidine has shown antibiotic activity against small-colony variants of S. aureus. We herein report the first study of the structure–activity relationship of tomatidine against S. aureus.

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