Absence of tmRNA increases the persistence to cefotaxime by upregulating the metabolites GlcNAc in Aeromonas veronii

Bacterial persisters refer to a small proportion of phenotypically heterogeneous variants with transient capability for survival when exposing to high concentrations of antibiotic, which constitute the major cause for recurrent infections both in human and aquatic infections. In pathogenic bacteria Aeromonas veronii, tmRNA (transfer-messenger RNA), the core factor of trans-translation system, was identified as a determinant regulator mediating the persistence to β-lactams. Compared with the wild type, the deletion of tmRNA exhibited unchanged growth rate, sustained susceptibility to cefotaxime, but did increase persister cell formation. Transcriptomic and metabolomic analyses revealed that, the absence of tmRNA not only upreglated the expressions of metabolic genes especially in the metabolic flux of peptidoglycan biosynthesis, but also significantly elevated the intercellular level of metabolite GlcNAc, thereby intensifying the contents of peptidoglycans in the cell wall. Eventually, exogenous GlcNAc stimulated significantly the bacterial growth and persistence to cefotaxime in a concentration dependent manner. Taken together, these results uncover a novel mechanism of persister formation mediated by tmRNA against the β-lactam challenges.