Functional proteomic analysis reveals <i>mglB</i> -mediated meropenem resistance and its reversal by galactose

Salmonella enteritidis is a globally prevalent zoonotic pathogen with a broad host range and high pathogenicity, ranking among the most common serotypes within the <i>Salmonella genus</i>. The widespread and often indiscriminate use of antibiotics has driven a continual rise in antimicrobial resistance among S. Enteritidis strains, posing a significant threat to public health. In this study, we employed a quantitative proteomics approach to investigate differential protein expression between meropenem-sensitive and -resistant S. Enteritidis strains. Bioinformatic analyses revealed significant downregulation of all the genes associated with the bacterial chemotaxis pathway in the resistant strain. To further explore the functional relevance of this pathway, we generated deletion mutants of 15 chemotaxis-related genes and assessed their susceptibility to meropenem. Notably, deletion of the <i>mglB</i> gene was associated with increased resistance. Given the known role of <i>mglB</i> in galactose transport, we hypothesized and subsequently confirmed that exogenous galactose supplementation enhances the bactericidal activity of meropenem against resistant strains. This synergistic effect was further validated in animal infection models. Collectively, these findings provide novel insights into the molecular basis of meropenem resistance in S. Enteritidis and highlight the potential of metabolic modulation as a strategy to restore antibiotic efficacy.