Targeting the cysteine desulfhydrase-derived H2S: A phytochemical gallic acid as a synergistic agent against S. Typhimurium infection.

The emergence of antimicrobial-resistant Salmonella Typhimurium (S. Typhimurium) has compromised clinical treatment and motivated development of alternative therapies. Suppression of bacterial hydrogen sulfide (H2S) production, an established survival mechanism under antibiotic and oxidative stress, offers a promising strategy for antimicrobial therapy. In S. Typhimurium, cysteine desulfhydrase (CDSH) is a key enzyme for H₂S production via L-cysteine degradation. However, the precise role of CDSH in stress tolerance and infection has not been fully defined, nor have inhibitors targeting CDSH been reported. Herein, we showed that genetic deletion of cdsH reduced S. Typhimurium tolerance to hydrogen peroxide (H2O2), potassium permanganate (KMnO4), heat stress, and antibiotics stress. And mechanistic study further revealed that CDSH-derived H2S enhanced the activity of the catalase KatE, which mediated the detoxification of H2O2 by endogenous H2S. Therefore, we extended our efforts to develop CDSH-targeting agents, and identified gallic acid (GA) as a CDSH inhibitor to effectively potentiate the activity of antibiotics in vitro and in vivo. Furthermore, molecular docking indicated that GA interacts with the catalytic pocket of CDSH, suggesting a potential mechanism for its inhibitory effect. Together, these results establish CDSH-mediated H2S production as a key determinant of S. Typhimurium stress tolerance, and GA as a CDSH inhibitor for adjunctive therapies against S. Typhimurium infection.