Curcumin derivatives exert a paradoxical antibacterial strategy by inducing a programmed way of cell death in Staphylococcus aureus.

It is a challenge for the health care system to develop potential alternative antibacterial strategies at the molecular viewpoints for combating emerging threat of antibiotic resistance. Beside various proposed alternatives, currently bacterial inbuilt programmed cell death process (PCD) is now being considered as potential target. Herein, our synthesized curcumin based pyran annulated bioactive compounds, with their specific structural standpoints, showed significant antibacterial efficacy against Staphylococcus aureus with PCD as the central mechanism. The compounds hindered bacterial growth with pronounced loss of virulence and cell death at very low dose through membrane disruption and electrolyte leakage. By optimum utilization of PCD, the compounds could change the altruistic behavior of the bacteria towards dissociated biofilm structure with loss of pathogenesis. Inside the bacterial cell, eukaryotic apoptosis like mechanism was identified, and was found to be regulated by cidA, lrgA, and PG hydrolase as the key players. These derivatives were also capable to reduce the S. aureus induced infection in vivo. Overall, this study reveals a PCD-guided alternative therapeutic strategy against staphylococcal infections using such modified phytochemicals, which can be implied to evade antibiotic resistance.