Public antibiotic resistance mechanisms in Salmonella can maintain inhibition by probiotics during antibiotic treatment

Probiotics are being explored as a sustainable alternative to antibiotics that can also inhibit antibiotic-resistant pathogens. However, probiotics generally show a lower killing efficacy against susceptible pathogens compared to traditional antibiotics. Combining probiotics with antibiotics could provide a solution: the antibiotic effectively clears infection caused by non-resistant pathogens, whereas the probiotic helps control infections involving antibiotic-resistant strains. However, since probiotic strains preferentially do not carry antibiotic-resistance mechanisms themselves in order to limit the further spread of antibiotic resistance, combinatorial treatment would also inhibit the probiotic, thereby severely limiting its efficacy. We explore the potential of a novel combination therapy that aims to exploit public antibiotic resistance mechanisms commonly found in pathogens. These public resistance mechanisms, such as β-lactamase enzymes and chloramphenicol acetyltransferases, can protect nearby susceptible cells from the antibiotic by detoxifying the local environment. We demonstrate that a β-lactamase-producing Salmonella Typhimurium can protect two distinct probiotic bacteria, Escherichia coli Nissle 1917 and Bacillus subtilis , against high concentrations of cefotaxime across a range of in vitro conditions, maintaining the inhibitory effect of the probiotic on Salmonella. We show that susceptible probiotic strains can retain their activity in the presence of otherwise inhibitory antibiotic concentrations by exploiting β-lactamase-mediated detoxification by Salmonella Typhimurium. These findings provide a conceptual framework for designing synergistic probiotic–antibiotic treatments, offering a potentially promising strategy for managing infections in the context of rising antibiotic resistance.