Metabolic reprogramming of the glutathione biosynthesis modulates the resistance of Salmonella Derby to ceftriaxone

Salmonella, a foodborne pathogen, has become a major public health concern because of its widespread drug resistance, including resistance to multiple drugs such as third-generation cephalosporin, ceftriaxone (CRO). However, the metabolic profile changes and associated mechanisms engendered by cephalosporin-resistant mutations remain uncharted. In this study, we have employed the LC-MS/MS metabolomics platform to determine the metabolic profiles of 138 strains of Salmonella. Our results show that metabolic profiles correspond to specific serotypes, sources, processing stages, and antibiotic resistance patterns. Notably, we observed that Salmonella Derby (S. Derby) with drug resistance to CRO has a different metabolic status with changes in glutathione biosynthesis. Specifically, glutathione oxidized (GSSG) and citrulline abundances are greatly suppressed in CRO-resistant S. Derby. Furthermore, exogenous GSSG or citrulline, but not glutathione reduced (GSH), restored the susceptibility of multidrug-resistant S. Derby to CRO. This study establishes a strategy based on functional metabolomics to manage the survival of antibiotic-resistant bacteria.