Key physiological and metabolic characteristics for the differentiation of quiescent Salmonella's cells into persisters

A prevalent tactic employed by bacteria to enhance their survival in challenging conditions, such as antibiotic exposure, involves entering a state known as quiescence. This state entails reversible arrest of cell growth, providing protection against various environmental stressors. Bacterial quiescence is of paramoubnt importance, particularly in Salmonella enterica serovar Typhimurium (S. Typhimurium), where the alternative sigma subunit of RNA polymerase, sigma S/RpoS, plays a crucial role in reshaping gene expression for stress resistance. Quiescent populations of bacteria can differentiate into persisters, surviving lethal antibiotic concentrations, which worsens antibiotic resistance issues. Understanding the mechanisms behind persister formation is crucial for drug development.

The study explores the interaction between sigma S and succinate dehydrogenase (Sdh) in persister formation at metabolic systems level.

Sdh, a membrane-bound complex connecting the TCA cycle and respiratory chain, is negatively regulated by sigma S, and its downregulation contributes to persister formation. This study aimed hence to understand the formation of antibiotic-resistant persister cells by characterizing the functional complementation of the Δsdh mutation by the ΔrpoS mutation. The main findings are that i) persister formation is more efficient in rich medium than in minimal medium, with certain metabolic characteristics favoring persister formation in rich medium affected by the Δsdh mutation, ii) succinate accumulation in the Δsdh mutant revealed by quantitative metabolomcs, with fumarate also accumulating, indicating the presence of an alternative pathway, iii) the ΔsdhΔrpoS mutant metabolizes succinate despite the absence of Sdh, suggesting compensation by an alternative pathway negatively controlled by RpoS and, iv) the frdABCD locus encoding fumarate reductase appears to be involved in this alternative pathway, with biochemical studies needed to confirm its role.

Phegnon, L., Uttenweiler-Joseph, S., & Létisse, F. (2024). EXTRAMETABOLOME ANALYSIS OF SALMONELLA corC MUTANTS BY NMR [Data set]. Zenodo. https://doi.org/10.5281/zenodo.10908202