The Impact of Endogenous Hydrogen Sulfide on Bacterial Resistance.

Infectious diseases, especially sepsis from bacterial infections, significantly threaten global health, with antimicrobial resistance (AMR) complicating treatment and increasing clinical burdens. Antibiotic overuse contributes to AMR by creating selective pressure, reducing the efficacy of traditional therapies, and necessitating new approaches. Endogenous hydrogen sulfide (H2S), a gaseous signaling molecule produced by most bacteria through cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST), plays a crucial role in bacterial resistance. This review explores the biological functions of bacterial endogenous H2S and its impact on AMR. H2S enhances resistance by neutralizing antibiotic-induced reactive oxygen species (ROS), reducing oxidative stress and DNA damage, and promoting biofilm formation, which obstructs antibiotic penetration and facilitates resistance gene exchange. Furthermore, enhancing H2S-based assays could significantly improve the diagnosis of AMR. Additionally, strategies such as targeting H2S metabolism-through the use of H2S synthase inhibitors or disrupting biofilms via H2S clearance-or the combination of H2S synthase inhibitors with antibiotics, may reverse resistance. A deeper understanding of the mechanisms by which H2S mediates resistance is essential for the development of advanced diagnostic tools and innovative therapies to combat AMR. Its clinical translation may reverse AMR passivity, guide antibiotic sensitizer development, and optimize therapies, holding significant clinical and translational value.