Supersulfides in bacterial antibiotic resistance: chemical inactivation, redox signaling, and translational opportunities.

The global spread of antimicrobial-resistant bacteria has emerged as one of the most pressing public health challenges worldwide. Because the development of novel antibiotics remains slow and increasingly difficult, innovative therapeutic strategies are urgently needed. Supersulfides, including persulfides and polysulfides, are ubiquitous sulfur species found in both prokaryotes and eukaryotes. Owing to their exceptional nucleophilicity and antioxidant capacity, they play central roles in cellular redox signaling and stress adaptation. Recent studies have further revealed that bacterial supersulfides contribute to antibiotic resistance through multiple mechanisms, including the direct chemical inactivation of β-lactam antibiotics, activation of multidrug efflux pumps, and detoxification of reactive oxygen species generated during antibiotic treatment. These findings identify bacterial supersulfide biosynthetic pathways as promising targets for the development of next-generation antimicrobial therapies. In this Review, we summarize current knowledge of supersulfide biosynthesis, with particular emphasis on recently identified pathways unique to bacteria. We also discuss the diverse mechanisms by which bacterial supersulfides promote antibiotic resistance and highlight recent advances in pharmacological strategies targeting supersulfide biosynthesis. Finally, we discuss the translational potential of targeting bacterial supersulfide metabolism and the key challenges that must be overcome for clinical application.