Metabolism-dependent succinylation governs resource allocation for antibiotic resistance
Jiahan Wu, Jiahan Wu, Xuan-wei Chen, Yingli Liu, Jinhua Wu, Jinhua Wu, Zhuang‐Gui Chen, Bo Peng
Abstract
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.