Flufenamic acid fosters bacterial clearance by inhibiting Staphylococcus aureus AgrA and NLRP3 inflammasome of phagocytes.

Abstract

The emergence of multi-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), poses a significant global health crisis. Antibiotic treatments are increasingly ineffective, particularly against intracellular bacteria. This study unveils the therapeutic potential of flufenamic acid (FFA) against MRSA infections and its underlying mechanism of bacterial clearance in phagocytes. Our findings demonstrate that FFA suppresses toxin production by targeting the Agr pathway in an AgrA-dependent manner and triggers the production of reactive oxygen species (ROS) in immune cells through a mitochondrial cAMP-mediated mechanism. Additionally, FFA concurrently inhibits NLRP3, thereby enhancing bacterial clearance by immune cells. In vivo efficacy was evaluated using various staphylococcal infection models, demonstrating FFA's ability to potentiate bacterial clearance. Moreover, FFA synergizes with gentamicin both in vitro and in vivo. These findings strongly support FFA as a promising candidate for novel therapeutic agents against MRSA infections.