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.