Bactericidal activity of the bacterial ATP synthase inhibitor tomatidine and the combination of tomatidine and aminoglycoside against persistent and virulent forms of Staphylococcus aureus

Tomatidine (TO), a phytomolecule, exerts a strong bactericidal activity on the infection-persistent phenotype of Staphylococcus aureus, the small-colony variant (SCV), with a minimal inhibitory concentration (MIC) of 0.06 ug/ml. In addition, the combination of TO to an aminoglycoside (AMG) shows a strong synergistic effect against prototypical (WT) S. aureus (MIC 0.06 ug/ml), which is otherwise unaffected by TO alone (MIC >128 ug/ml). We have recently established that the ATP synthase (subunit AtpE) was the molecular target of TO and that TO reduces the production of ATP in S. aureus. The purpose of this study was to understand how TO and the TO-AMG combination exert bactericidal activities against S. aureus SCV and WT strains, respectively.