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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