Guttiferone E from Brazilian red propolis inhibited wound-isolated methicillin-resistant Staphylococcus aureus and enhanced the bactericidal action of suppressed macrophages

Background: Propolis has been traditionally used to treat inflammatory and infectious diseases, and it is still used and researched worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) may cause invasive infections and propolis anti-MRSA activity has been analyzed. Purpose: A standardized red propolis extract (SRPE), its benzophenones-rich fraction (BRF), and isolated benzophenones (guttiferone E - GUT E, and oblongifolin B - OBL B) were assayed for their antibacterial and immunomodulatory action. Methods: Formulations (BRP28, BRP29, BRP150, BRP153, and BRPLUS) were prepared and their minimum inhibitory concentrations (MIC) were assessed. The synergistic action of GUT E with antimicrobials was evaluated on a wound-isolated MRSA, as well as the inhibition of biofilm formation by the formulations (BRP28 and BRP29) and GUT E. Tohoku Hospital Pediatrics-1 (THP-1) cells were used to investigate cytokine production and the bactericidal activity of suppressed macrophages against MRSA. Computational predictions were performed with GUT E and antimicrobials to observe their interaction with the active and allosteric site of penicillin-binding protein 2a (PBP2a). Results: SRPE and BRF were not efficient against MRSA while GUT E and OBL B exerted a potent activity. GUT E exerted a synergistic effect with carbapenems and vancomycin. BRP28, BRP29, and GUT E inhibited biofilm formation and increased the antibacterial capacity of suppressed macrophages, with no differences in cytokine production. GUT E showed a high binding affinity to PBP2a. Conclusion: GUT E exhibited a direct anti-MRSA activity and indirectly enhanced the macrophage bactericidal activity. Molecular docking suggested that GUT E has a versatile interaction with PBP2a.