Proteome trade-off between primary and secondary metabolism shapes acid stress induced bacterial exopolysaccharide production

Abstract

Bacterial exopolysaccharide (EPS), as a high-value probiotic product, is known to be biosynthesized by a secondary metabolic pathway to mediate acid stress in lactic acid bacteria. However, a quantitative understanding of cellular resource coordination underlying acid stress-induced EPS production remains lacking. Systematically investigating Lactiplantibacillus plantarum HMX2, a well acknowledged EPS-producer, this study measured growth phenotypes, metabolomics, and proteomics of the target strain cultured at different pH values. Multi-omics analysis demonstrated that the EPS biosynthetic pathway was significantly up-regulated under acid stress, and pinpointed Fur as the most probable controlling transcriptional factor. Furthermore, the experimentally observed proteome re-allocation between primary metabolism and EPS biosynthesis was effectively captured by the regulatory proteome constrained flux balance analysis (RPCFBA) model via incorporating an activation function for secondary metabolism. This work, fusing the power of multi-omics analysis and genome-scale metabolic modeling, quantitatively elucidated the proteome trade-off between cellular growth and stress resistance underlying EPS production in lactic acid bacteria and shed light on the control principle of microbial secondary metabolism.