H2S, Friend or Foe?

Hydrogen sulfide (H₂S) is an important gasotransmitter in all mammals. Recent studies demonstrate that bacteria-derived H₂S functions as a universal defense against antibiotic insult. In addition, H₂S contributes to the formation of biofilm, and a much higher level of H₂S is detected in persister cells. The inhibition of H₂S biogenesis yields antibacterial sensitization with antibiotics against both sensitive and persister cells. Because different strains of bacteria rely on different H₂S-synthesizing enzymes (CBS/CSE/3-MST) to produce H₂S, it is imperative to devise pan-inhibitors for general application. However, the development of such pan-inhibitors is exceedingly challenging, and no precedents have been reported. Moreover, there also exists a non-enzymatic pathway for H₂S production, for which enzyme inhibitors show no effects.

To tackle these challenges, Prof. Xingyue Ji’s group proposes an alternative strategy, which capitalizes on the specific reaction between the H₂S scavenger and H₂S to deplete bacteria-derived H₂S. In collaboration with Prof. Yipeng Wang, they studied the antibacterial sensitization effects of these newly developed H₂S scavengers both in vitro and in vivo, and the results are recently published in Nature Communications, entitled “H₂S scavenger as a broad-spectrum strategy to deplete bacteria-derived H₂S for antibacterial sensitization”.

By devising a specific H₂S scavenger, the bacteria-derived H₂S can be efficiently depleted irrespective of H₂S sources, achieving general antibacterial sensitization with antibiotics against any H₂S-producing bacterial strains. Briefly, a small condensed small-molecule compound library was screened using a tandem methylene blue and lead acetate strip assay, and a small molecule was identified as the hit compound. After a detailed structural optimization campaign, a lead compound 7b was successfully identified, which displayed very pronounced H₂S-depletion activity in a series of bacteria including MRSA, E. coli, S. aureus and P. aeruginosa. Importantly, it can also efficiently sensitize the bacteria to the treatment of bactericidal agents, enhance bacterial clearance of macrophages, eradicate biofilm, and sensitize persister cells to antibiotics both in vitro and in vivo. In aggregate, this work describes a new strategy to downregulate bacterial H₂S levels for general antibacterial sensitization, provides another layer of evidence to support H₂S biogenesis as a viable target for antibacterial adjuvant design and delivers a promising candidate compound for further development.

The master students Jiekai Sun, Ye Gao, Shuangyu Li, and the PhD student Xu Wang shared the lead authorship. The corresponding authors are Profs. Xingyue Ji, Yipeng Wang, and Wei Zhang.

Reference: 

Sun, J., Wang, X., Gao, Y. et al. H₂S scavenger as a broad-spectrum strategy to deplete bacteria-derived H₂S for antibacterial sensitization. Nat Commun 15, 9422 (2024).

Corresponding authors:

Dr. Xingyue Ji is an extinguished professor at the College of Pharmaceutical Sciences, Soochow University. He is also the Chair of the Department of Medicinal Chemistry. His research interests encompass the development of novel decaging chemistry (in particular bioorthogonal cleavage chemistry) for prodrug design. He has published over 60 papers in high-profile journals, such as Nature Chemistry, Nature Commun., J. Am. Chem. Soc., Angew. Chem., J. Med. Chem., to name a few.

Dr. Yipeng Wang is a professor at the College of Pharmaceutical Sciences, Soochow University. His research focuses on the discovery of natural medicinal peptides/proteins, the design and application of medicinal peptides/proteins, and the study of innate immunity. He has published over 70 peer-reviewed articles in high-impact journals, including Nat Commun (2024), Med Res Rev (2024, 2022), J Med Chem (2023, 2022, 2018a, 2018b), Small (2023), J Biol Chem (2015), and ACS Infect Dis (2020). Two of his papers are recognized as ESI Highly Cited Papers, and his work has garnered over 2,400 citations, with one paper cited more than 290 times (Google Scholar). He has an H-index of 28. Prof. Wang holds more than 60 granted national invention patents and has led over 10 projects, including three funded by the National Natural Science Foundation of China and several key initiatives under the Jiangsu Provincial Key Research and Development Program. He has been honored as a high-level talent in Fujian Province, an outstanding young faculty member in Jiangsu Province's Qinglan Project, a leading entrepreneurial talent in Xiamen’s Double Hundred Plan, and a high-demand expert in regions such as the Yellow River Delta and Suzhou.