Effects of l-Serine on Macrolide Resistance in Streptococcus suis

Streptococcus suis is an important zoonotic pathogen. Due to the indiscriminate use of macrolides, S. suis has developed a high level of drug resistance, which has led to a serious threat to human and animal health. However, it takes a long time to develop new antibacterial drugs. Therefore, we consider the perspective of bacterial physiological metabolism to ensure that the development of bacterial resistance to existing drugs is alleviated and bacterial susceptibility to drugs is restored. In the present study, an untargeted metabolomics analysis showed that the serine catabolic pathway was inhibited in drug-resistant S. suis. The addition of l-serine restored the fungicidal effect of macrolides on S. suis in vivo and in vitro by enhancing the serine metabolic pathway. Further studies showed that l-serine, stimulated by its serine catabolic pathway, inhibited intracellular H₂S production, reduced Fe-S cluster production, and restored the normal occurrence of the Fenton reaction in cells. It also attenuated the production of glutathione, an important marker of the intracellular oxidation-reduction reaction. All these phenomena eventually contribute to an increase in the level of reactive oxygen species, which leads to intracellular DNA damage and bacterial death. Our study provides a potential new approach for the treatment of diseases caused by drug-resistant S. suis. IMPORTANCE The emergence of antimicrobial resistance is a global challenge. However, new drug development efforts consume considerable resources and time, and alleviating the pressure on existing drugs is the focus of our work. We investigated the mechanism of action of l-serine supplementation in restoring the use of macrolides in S. suis, based on the role of the serine catabolic pathway on reactive oxygen species levels and oxidative stress in S. suis. This pathway provides a theoretical basis for the rational use of macrolides in clinical practice and also identifies a possible target for restoring drug sensitivity in S. suis.