Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.

The mechanisms that organisms allocate resources to sustain biological phenotypes remain largely unknown. Here, we use mobilized colistin resistance (mcr-1), which modifies lipopolysaccharide (LPS) to confer colistin resistance, as a model to explore how bacteria reallocate resources to support mcr-1-mediated resistance. We show that bacteria redirect resources from glycolysis, the pyruvate cycle, and LPS biosynthesis toward glycerophospholipid metabolism to produce phosphatidylethanolamine, the substrate for mcr-1 to modify LPS, while reducing LPS content to limit colistin binding. This reallocation down-regulates succinyl-coenzyme A (CoA) to diminish succinylation of proteins including triosephosphate isomerase (TPI), CpxR, and PdhR, thereby sustaining resistance. Exogenous succinate or α-ketoglutarate restores succinylation in a succinyl-CoA-dependent manner. Succinylation of TPI redirects metabolic flux to glycolysis and the pyruvate cycle, while succinylation of CpxR and PdhR up-regulates LPS biosynthesis, ultimately attenuating colistin resistance. Thus, we reveal a previously unrecognized mechanism by which bacteria regulate resource allocation through metabolism-driven posttranslational protein modification, offering strategies to combat antibiotic resistance.