Malonate Modulates Macrophage Lipids to inhibit Mycobacterium avium Growth and Enhance Drug Efficacy
The rising incidence of Mycobacterium avium complex (MAC) pulmonary disease highlights the need for novel therapeutic strategies. Mycobacterium species reprogram macrophage lipid metabolism, inducing excessive triacylgycerol (TG) accumulation and foamy macrophage formation, which supports bacterial survival. Here, we investigate malonate, a competitive inhibitor of succinate oxidation and an intermediate in lipid metabolism, as a potential metabolic modulator in MAC infection. Treatment with dimethyl malonate (DMM), a malonic acid derivative, enhanced macrophage-mediated MAC clearance by restoring lipid homeostasis. Multi-omics analyses revealed that DMM treatment significantly upregulates acyl-CoA thioesterase 1 (ACOT1), a key enzyme involved in lipid metabolism. ACOT1 activation promotes both TG synthesis and lipolysis to counteract MAC-induced metabolic dysregulation. DMM also exhibited the strongest synergy with clofazimine among tested adjunctive agents, significantly reducing TG accumulation and enhancing bacterial clearance. These findings establish host-directed metabolic modulation as a promising strategy to combat MAC infection, potentially improving immune function and enhancing antimicrobial efficacy. This study provides a foundation for targeting host lipid metabolism in MAC and other intracellular bacterial infections.