Discovery of Metabolic Reprogramming 2-Quinolones as Effective Antimicrobials for MRSA-Infected Wound Therapy.

To date, the abuse of antibiotics and a gradual decline in novel antibiotic discovery enlarge the threat of drug-resistant bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA). Herein, inspired by the unique structures and antibacterial activities of 2-quinolones, a class of novel 2-quinolones with substituted pyridines was synthesized. Notably, compound 11, the derivative with a methylpyridine fragment, showed potent antibacterial and antibiofilm activities, especially for MRSA strains (MIC = 0.02-0.04 μg/mL). A mechanistic study of compound 11 revealed that the increase of intracellular ROS and acceleration of the TCA cycle, which reprogrammed the bacterial metabolism, eventually triggered membrane damage and bacterial death. Most importantly, compound 11, with antibacterial and anti-inflammatory properties, accelerated the reconstruction and healing of MRSA-infected cutaneous wounds by decreasing bacterial loads, attenuating inflammation, and promoting angiogenesis. Overall, these findings provide a novel multifunctional chemotype with broad-spectrum antibacterial activity and highlight a promising strategy for MRSA-infected wound healing.