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

Bacteria-derived HS plays multifunctional protective roles against antibiotics insult, and the HS biogenesis pathway is emerging as a viable target for the antibacterial adjuvant design. However, the development of a pan-inhibitor against HS-synthesizing enzymes is challenging and underdeveloped. Herein, we propose an alternative strategy to downregulate the HS levels in HS-producing bacteria, which depletes the bacteria-derived HS chemically by HS scavengers without acting on the synthesizing enzymes. After the screening of chemically diversified scaffolds and a structural optimization campaign, a potent and specific HS scavenger is successfully identified, which displays efficient HS depletion in several HS-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 HS 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 HS and establish the HS biogenesis pathway as a viable target for persisters and drug-resistant bacteria, but also deliver a promising antibacterial adjuvant for potential clinical translation.