H2S Scavenger as A Universal Strategy to Deplete Bacteria-derived H2S for Antibacterial Sensitization

Bacteria-derived H2S plays multifunctional protective roles against antibiotics insult, and H2S biogenesis pathway is emerging as a viable target for the antibacterial adjuvant design. However, the development of a pan-inhibitor against H2S-synthesizing enzymes is exceedingly challenging and severely underdeveloped. Herein, we propose an alternative strategy to downregulate the H2S levels in H2S-producing bacteria, which depletes the bacteria-derived H2S chemically by H2S scavengers without acting on the synthesizing enzymes. After the screening of chemically diversified scaffolds and a structural optimization campaign, a potent and specific H2S scavenger was successfully identified, which displayed efficient H2S depletion in several H2S-producing bacteria, potentiated both bactericidal agents and photodynamic therapy, enhanced the bacterial clearance of macrophages, disrupted the formation of bacterial biofilm and increased the sensitivity of bacterial persister cells to antibiotics. Most importantly, such an H2S scavenger exhibited very pronounced synergistic effects with gentamicin in a methicillin-resistant Staphylococcus aureus (MRSA) infected peritonitis mouse model. In aggregate, our results not only provided an effective strategy to deplete bacteria-derived H2S and firmly established the H2S biogenesis pathway as a viable target for persisters and drug-resistant bacteria, but also delivered a promising antibacterial adjuvant for potential clinical translation.