Hydrogen sulfide (H2S) is a gaseous signaling molecule which plays important roles in physiological and pathological processes. Notably, endogenously produced H2S has been recently recognized as a general protective molecule, which renders multiple bacterial species highly resistant to oxidative stress, host immune responses and antibiotics. Therefore, understanding the mechanisms underlying H2S-mediated resistance would help in developing new therapeutic strategies against human pathogens and antibiotic resistance, a serious public health problem worldwide.
In E.coli, H2S is enzimatically produced by 3-mercaptopyruvate sulfurtransferase (3MST), an enzyme belonging to the family of the sulfurtransferases. In addition to H2S production, the 3-MST contribute to the production of H2S-derived species, persulfides and polysulfides, which have an important cellular protection from oxidants. Remarkably, this enzyme appears crucial in the defence against hydrogen peroxide and in antimicrobial resistance in E. coli, including clinical pathogenic strains.
Our working hypothesis is that MST endows E.coli with the ability to successfully resist nitric oxide and its derived species which are produced by the host macrophages to counteract infections.
In this project I will study the role of MST in the bacterial response to nitrosative stress by using E.coli wild type and MST mutant strains to understand the molecular mechanisms that drive cytoprotection in E.coli, and possibly other pathogens, under stress conditions allowing survival, growth and host colonization.
By elucidating these mechanisms, I will contribute to the understanding of the bacterial strategies to combat host chemical weapons as well as the role of sulfide and its derived species within the framework of host-microbe relationships.
Many recent works have demonstrated that H2S and downstream RSS may enhance
bacterial survival in a hostile microenvironment, regulate biofilm dynamics, confer resistance against myriad oxidative stressors like antibiotics. Antibiotic resistance in particular is a serious public health problem worldwide and the absence of effective pharmacological therapies has prompted research and characterization of novel targets for the development of radically novel antimicrobials. Targeting the H2S metabolic enzymes is now receiving a strong interest as an innovative strategy for efficient interventions in infectious diseases. [1]
In E.coli, MST has been recently shown to contribute to the production of H2S and reactive sulfane sulphur [2], a type of RSS with zero-valent sulfur such as persulfides and polysulfides, important for both regulation of the amount of bioavailable sulphide, as it can liberate H2S ¿on demand, and cellular protection from oxidants.
Since bacteria may experience NO exposure during infection in addition to H2S, potential interactions between these two gases may affect cellular metabolism and cellular responses to environmental condition changes.The role of these interactions in bacterial pathogenesis is debated and in E.coli remains to be explored.
The principal purpose of this research project is to determine the role of MST in the bacterial response to nitrosative stress to understand the molecular mechanisms that drive cytoprotection of E.coli, and possibly other pathogens,cells under stress conditions allowing survival, growth and colonise the host colonization.
Elucidating these potential mechanisms we will contribute to the understanding of the bacterial strategies to combat the host molecular weapons favouring its colonization, The characterization of new biochemical pathways required for the success of infections is important better understand the host-pathogen relationships and shed some new light on bacterial pathogenesis.
[1] Brenna J. C. Walsh1 and David P. Giedroc, J. Biol. Chem.295(38),13150-13168 (2020)
[2] Li Kai, et al., Front. Microbiol., 10:298 (2019)