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

食腐动物 敏化 广谱 细菌 微生物学 化学 生物 计算生物学 免疫学 遗传学 生物化学 组合化学 激进的
作者
Jingfeng Sun,Xu Wang,Ye Gao,Shuangyu Li,Ziwei Hu,Yan Huang,Baoqiang Fan,Xia Wang,Lei Zhu,Chunhua Qiao,Wei Zhang,Yipeng Wang,Xingyue Ji
出处
期刊:Nature Communications [Nature Portfolio]
卷期号:15 (1)
标识
DOI:10.1038/s41467-024-53764-7
摘要

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. Bacteria-derived H2S functions as a universal defense against antibiotics challenge. Here, Ji et al developed a broad-spectrum H2S scavenger that efficiently removes endogenous H2S in several bacteria, disrupts biofilm formation and sensitizes persister cells to antibiotic-mediated killing in vitro and in vivo.
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