H2S scavenger as a broad-spectrum strategy to deplete bacteria-derived H2S for antibacterial sensitization

Abstract

Bacteria-derived H₂S plays multifunctional protective roles against antibiotics insult, and the 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 challenging and 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 is successfully identified, which displays efficient H₂S depletion in several H₂S-producing bacteria, potentiates both bactericidal agents and photodynamic therapy, enhances the bacterial clearance of macrophages and polymorphonuclear neutrophils, disrupts the formation of bacterial biofilm and increases the sensitivity of bacterial persister cells to antibiotics. Most importantly, such an H₂S scavenger exhibits sensitizing effects with gentamicin in Pseudomonas aeruginosa -infected pneumonia and skin wound female mouse models. In aggregate, our results not only provide an effective strategy to deplete bacteria-derived H₂S and establish the H₂S biogenesis pathway as a viable target for persisters and drug-resistant bacteria, but also deliver a promising antibacterial adjuvant for potential clinical translation.