Thymol mediates bactericidal activity against Staphylococcus aureus by targeting an aldo-keto reductase and consequent depletion of NADPH

Staphylococcus aureus is a common pathogen that can cause life-threatening infections. Treatment of antibiotic-resistant S. aureus infection needs effective antibacterial agents. Thymol, a generally recognized safe natural compound, has the potential as an alternative to treat S. aureus infections. However, the targets and mechanisms of action of thymol were not fully understood. Bioinformatics analysis showed that IolS, a predicted aldo-keto reductase (AKR) in S. aureus, could be a potential target of thymol. Isothermal Titration Calorimetry (ITC) analysis demonstrated that thymol directly binds IolS and amino acid residues (Y30A and L33A) are essential for such binding. Deletion of IolS or mutation of Y30A and L33A reduced the bactericidal activity of thymol at the concentration of 200 µg/ml, suggesting that thymol mediates bactericidal activity via binding with IolS. Biochemical analysis showed that addition of thymol significantly increased AKR activity of IolS from 1.6±0.1 U to 2.4±0.2 U (P<0.05). Th...