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

Jiekai Sun, Xu Wang, Ye Gao, Shuangyu Li, Ziwei Hu, Yan Huang, Baoqiang Fan, Xia Wang, Miao Liu, Chunhua Qiao, Wei Zhang (), Yipeng Wang () and Xingyue Ji ()
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Jiekai Sun: Soochow University
Xu Wang: Soochow University
Ye Gao: Soochow University
Shuangyu Li: Soochow University
Ziwei Hu: Soochow University
Yan Huang: Soochow University
Baoqiang Fan: Shandong University
Xia Wang: Soochow University
Miao Liu: Soochow University
Chunhua Qiao: Soochow University
Wei Zhang: Shandong University
Yipeng Wang: Soochow University
Xingyue Ji: Soochow University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53764-7

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