| 描述信息 |
Antimicrobial resistance has emerged as a major global public health threat, underscoring the urgent need for novel therapeutic strategies. In this study, we demonstrate that protocatechualdehyde (PA), a natural compound derived from Salvia miltiorrhiza, exhibits potent and time-dependent bactericidal activity against ampicillin-resistant Escherichia coli. PA was also effective against AmpC β lactamase expressing strain and clinically isolated multidrug-resistant strains of E. coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, notably by synergizing with aminoglycoside antibiotics to overcome resistance. Mechanistically, integrated metabolomic and functional analyses reveal that PA induces a profound metabolic reprogramming in ampicillin resistant Escherichia coli, characterized by the hyperactivation of central carbon metabolism, with pyruvate catabolism serving as a critical hub. This forced metabolic flux leads to a surge in intracellular ATP and NADH, ultimately driving an overload of the electron transport chain and a lethal burst of ROS. Genetic and inhibition of the pyruvate dehydrogenase complex attenuates both ROS production and the bactericidal effect, confirming the causal link between metabolic disruption and bacterial death. PA treatment markedly improved survival and reduced bacterial burden in a murine systemic infection model, may posed application prospect. These findings provide a foundational rationale for developing PA based therapeutics or derivatives to combat multidrug-resistant Gram negative infections, particularly in combination with aminoglycoside antibiotics. |
