Abstract Methicillin‐resistant Staphylococcus aureus (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach is to develop ways to revitalize existing antibiotics. Here, we show that the phytogenic compound cinnamaldehyde (CIN) and β‐lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to β‐lactam therapy and inhibit MRSA biofilm formation. Mechanistic studies indicated that the CIN potentiation effect on β‐lactams was primarily the result of inhibition of the mecA expression by targeting the staphylococcal accessory regulator sarA. CIN alone or in combination with β‐lactams decreased sarA gene expression and increased SarA protein phosphorylation that impaired SarA binding to the mecA promoter element and downregulated virulence genes such as those encoding biofilm, α‐hemolysin, and adhesin. Perturbation of SarA–mecA binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to β‐lactams. Furthermore, CIN fully restored the anti‐MRSA activities of β‐lactam antibiotics in vivo in murine models of bacteremia and biofilm infections. Together, our results indicated that CIN acts as a β‐lactam adjuvant and can be applied as an alternative therapy to combat multidrug‐resistant MRSA infections.
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