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 <i>Staphylococcus aureus</i> (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 <b>11</b>, 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 <b>11</b> 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 <b>11,</b> 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.