3-Methylthiopropionic Acid Kills Carbapenem-Resistant Klebsiella pneumoniae by Disrupting Membrane Integrity and Bioenergetics

The rapid dissemination of New Delhi metallo-β-lactamase (NDM) genes, such as blaNDM-1 and blaNDM-5, has rendered carbapenems ineffective against Klebsiella pneumoniae, posing a severe public health threat. Here, we employ comparative metabolomics to reveal that NDM-mediated resistance is underpinned by profound metabolic reprogramming. From this altered metabolic landscape, we identify 3-methylthiopropionic acid (MTPA) as a potent endogenous metabolite capable of directly killing NDM-producing strains. MTPA exhibits rapid bactericidal activity in vitro and significantly improves survival in murine infection models. Mechanistically, MTPA disrupts membrane integrity, dissipates proton motive force, depletes intracellular ATP, and induces ROS accumulation via respiratory chain complex I inhibition. Integrated transcriptomics and metabolomics revealed a catastrophic collapse of central carbon metabolism, CoA biosynthesis, and redox homeostasis. This work establishes a chemical strategy to combat carbapenem resistance by targeting pathogen metabolic reprogramming.