Astrakurkurone targets multidrug resistant Staphylococcus aureus biofilms through ROS-mediated cell membrane damage and β-lactamase inhibition.

Methicillin-resistant Staphylococcus aureus (MRSA) pose a formidable health threat owing to their multidrug resistance (MDR) nature, robust biofilms and persistence. Natural product-based medications are a highly viable strategy for challenging MDR and biofilm persistence with diverse therapeutic benefits. In this study, the triterpenoid Astrakurkurone, previously purified from a wild edible mushroom Astraeus hygrometricus, showed antibacterial efficacy against MRSA BAA1717 and a clinical isolate (MRSA CI-1) with MICs ranging from 150 to 300 μg/mL. 1/2 MIC concentration of Astrakurkurone also inhibited 93.95% and 88.31% of MRSA BAA1717 and MRSA CI-1 biofilms through downregulating quorum sensing and virulence factors such as agrA, sarA, bap, sasG, icaA, and hla. The inhibition of staphyloxanthin production by Astrakurkurone was another interesting insight, sensitizing bacterial cells to reactive oxygen species (ROS). The accumulation of ROS was observed as one of the primary mechanisms of Astrakurkurone that affected potential and integrity of cell membrane. Intriguingly, Astrakurkurone acted as a β-lactamase inhibitor by downregulating blaZ expression by ∼11.11 fold. Moreover, a synergistic and additive interaction of Astrakurkurone with β-lactam antibiotic cefoxitin was evinced, supporting its β-lactamase inhibitory nature. Furthermore, the antibiotic-induced and biofilm-induced persister cells were eliminated by Astrakurkurone, providing another important insight for recurrent and chronic disease management. Astrakurkurone eradicated matured biofilms from urinary catheter, goat skin wound, skin burn wound and lung sections, strengthening applicability potential. In summary, the antibiofilm, antivirulence and antipersister nature of Astrakurkurone could emerge as a promising therapeutic alternative for the cure of medicinal implant-associated maladies, severe skin and lung infections with enhanced efficacy.