Sodium dehydroacetate confers broad antibiotic tolerance by remodeling bacterial metabolism

Antibiotic tolerance has been a growing crisis that is seriously threatening global public health. However, little is known about the exogenous factors capable of triggering the development of antibiotic tolerance, particularly in vivo. Here we uncovered that an previously approved food additive termed sodium dehydroacetate (DHA-S) supplementation remarkably impaired the activity of bactericidal antibiotics against various bacterial pathogens. Mechanistic studies indicated that DHA-S induced glyoxylate shunt and reduced bacterial cellular respiration by inhibiting the enzymatic activity of alpha-ketoglutarate dehydrogenase (alpha-KGDH). Furthermore, DHA-S mitigated oxidative stress imposed by bactericidal antibiotics and enhanced the function of multidrug efflux pumps. These actions worked together to induce bacterial tolerance to antibiotic killing. Interestingly, the addition of five exogenous amino acids, particularly cysteine and proline, effectively reversed antibiotic tolerance elicited by DHA-S both in vitro and in mouse models of infection. Taken together, these findings advance our understanding of the potential risks of DHA-S in the treatment of bacterial infections, and shed new insights into the relationships between antibiotic tolerance and bacterial metabolism.

Automated summary

Antibiotic tolerance poses a serious threat to global public health and the exogenous factors triggering its development are not well understood. This study reveals that a food additive called sodium dehydroacetate (DHA-S) impairs the activity of bactericidal antibiotics by inhibiting bacterial cellular respiration and enhancing multidrug efflux pumps. The addition of specific amino acids can reverse antibiotic tolerance elicited by DHA-S. These findings enhance our understanding of the potential risks of using DHA-S in bacterial infection treatment and provide insights into the relationship between antibiotic tolerance and bacterial metabolism.