Gut News! ITQB NOVA Scientists Reveal Key Enzyme In Diarrhoea-Causing Bacteria
Oeiras, 22 December 2023
Ever had stomach problems while taking antibiotics? We all did. Antibiotics weaken the protective microbiota of your gastrointestinal tract. When our gut is more susceptible to infection, some microorganisms take the chance to infect it. Clostridioides difficile is the leading cause of diarrhoea linked to antibiotic therapy and is currently considered a global threat. Beside diarrhoea, infection can also lead to more serious complications, including bowel perforation and even death. A team of ITQB NOVA scientists, in collaboration with the University of Nottingham and Texas A&M University (in the United Kingdom and United States of America, respectively), have identified a key enzyme crucial for C. difficile colonization and infection of the intestine. This discovery may be the first steps for the development of prevention or treatment options, based on the inhibition of this enzyme.
Clostridioides difficile (C. difficile) is unable to survive in environments where oxygen is present. Therefore, it relies on oxygen-resistant spores to infect new hosts. These spores contain layers on its surface that protect them from attacks of antibodies or other proteins, allowing them to settle in the small intestine. When settled in, they start to germinate cells that release toxins that often lead to bowel issues, such as diarrhoea, but may have more serious consequences like pseudomembranous colitis (a severe inflammation of the large intestine), toxic megacolon, bowel perforation and in the most severe cases sepsis and death.
In an article published in PLOS Pathogens, the ITQB NOVA scientists identified an enzyme in these bacteria, called YabG, that plays crucial roles in several processes of the infection by C. difficile. Through a combination of computational, genetics, cell and structural biology methods and using a hamster as a model of infection, they uncovered previously unknown structural and functional characteristics of this enzyme. Not only did they find that YabG shows a unique structural organisation, but also that YabG plays a crucial role in spore formation and the subsequent germination in the host. According to Eleonora Marini, of the Microbial Development lab, “preventing the activity of this enzyme is a promising way to develop medications to prevent or mitigate the effects of infection by C. difficile”.
“This discovery unleashes several new pathways for the development of prevention or treatment options to tackle the infection by C. difficile and prevent its consequences on human health”, says Adriano O. Henriques, head of the Microbial Development Lab. “The next step is to assess whether inhibiting the activity of YabG really impairs its germination, colonisation and spreading in the organism and find which inhibitors work best”, adds Wilson Antunes, Major of The Portuguese Army. Moreover, they want to further explore the mechanisms of activity of YabG, given its unique organisation and its role on gene expression during spore development.
This multidisciplinary study is a collaboration of several ITQB NOVA labs, involving also the Dynamic Structural Biology Lab, led by Tiago Cordeiro, and the Multiscale Modeling Lab, led by Manuel Melo.
Sub-cellular localization of YabG by high-resolution fluorescence microscopy.
Funding: This work was supported by the European Union Marie Sklodowska Curie, Innovative Training Networks (contract number 642068) to AOH; PTDC/BIA-MIC/29293/2017 to MS from FCT (“Fundação para a Ciência e a Tecnologia") and 5R01AI116895 and 1U01AI124290 to J.A.S. from the National Institute of Allergy and Infectious Diseases; Project LISBOA-01-0145-FEDER-007660 (“Microbiologia Molecular, Estrutural e Celular”) funded by FEDER funds through COMPETE2020 – “Programa Operacional Competitividade e Internacionalização” (POCI).
Original paper
A sporulation signature protease is required for assembly of the spore surface layers, germination and host colonization in Clostridioides difficile
Eleonora Marini, Carmen Olivença, Sara Ramalhete, Andrea Martinez Aguirre, Patrick Ingle, Manuel N. Melo, Wilson Antunes, Nigel P. Minton, Guillem Hernandez, Tiago N. Cordeiro, Joseph A. Sorg, Mónica Serrano, Adriano O. Henriques
DOI: https://doi.org/10.1371/journal.ppat.1011741
