Tag: c. difficile

Categories : Diseases, Syndromes and ConditionsTags :

A New Clue to Disarming C. Difficile’s Toxic Weaponry

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C difficile. Source: CDC

Therapeutic interventions for Clostridioides difficile infection (CDI) could make use of a glucosyltransferase domain (GTD) as an ideal molecular target, potentially yielding new, effective treatments for this deadly disease.

The study, published in Science Advances, provided new insights into TcdB, the toxic molecular weaponry of C. difficile and its hypervirulent strains, creating an opportunity to disarm it.

CDI is the leading cause of antibiotic-associated diarrhoea and gastroenteritis-associated deaths worldwide, accounting for 500 000 cases and 29 000 deaths in the US every year and is classified by the Centers for Disease Control and Prevention as one of the top health threats. The emergence and spread of hypervirulent C. difficile strains is of global concern, resembling as it does the occurrence of new virus variants in current COVID pandemic. TcdB is one of two homologous C. difficile exotoxins, and TcdB alone is capable of causing the full spectrum of CDI diseases.

“We focused on the structure and function of TcdB’s crucial GTD, which is the toxin’s ‘warhead.’ The GTD is delivered by the toxin inside the host cells and causes most of the cytosolic damage to patients,” said corresponding author Rongsheng Jin, PhD, professor in the Department of Physiology & Biophysics at the UCI School of Medicine. “We discovered molecular mechanisms by which the GTD specifically recognises and blocks the physiological functions of the human GTPases Rho and R-Ras enzyme families that are crucial signaling molecules.”

The team also showed that the classic form of TcdB and the hypervirulent TcdB recognise their human targets in different ways, leading to distinct structural changes to the host cells caused by bacterial invasion.

“Once the GTD of TcdB is inside the cells, it is shielded by our cells and becomes inaccessible to passive immunotherapy. But our studies suggest that small molecule inhibitors could be developed to disarm the GTD, which will directly eliminate the root cause of disease symptoms and cellular damage,” Prof Jin explained. “This new strategy can potentially be integrated with and complement other CDI treatment regiments.”

Source: UCI School of Medicine

Categories : AgeingTags :

Centenarians’ Unique Microbiomes Protect Against Bacterial Infections

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Source: Miika Luotio on Unsplash

A new study has discovered that people who live to be 100 or older have a unique microbiome that may protect against certain bacterial infections  including those caused by multidrug-resistant bacteria. The findings, published in Nature, could point to new ways to treat chronic inflammation and bacterial disease.

A team of researchers studied microbes from  faecal samples of 160 Japanese centenarians who had an average age of 107. They found that centenarians, compared to people aged 85 to 89 and those between 21 and 55, had higher levels of several bacterial species that produce molecules called secondary bile acids. Secondary bile acids are generated by microbes in the colon and are thought to help protect the intestines from pathogens and regulate the body’s immune responses.

Next, the researchers treated common infection-causing bacteria in the lab with the secondary bile acids that were elevated in the centenarians. One molecule, called isoalloLCA, was found to strongly inhibit the growth of the  antibiotic-resistant bacterium Clostridioides difficile. Feeding mice infected with C. difficile diets supplemented with isoalloLCA similarly suppressed levels of the bacteria. The team also found that isoalloLCA potently inhibited or killed many other gram positive pathogens, suggesting that isoalloLCA may play a role in keeping the delicate equilibrium of microbial communities in a healthy gut.

“The ecological interaction between the host and different processes in bacteria really suggests the potential of these gut bugs for health maintenance,” said Plichta, a computational scientist at the Broad.

Additional studies from different regions around the world with more participants and longer duration could help find a causal link between longevity and bile acids. The bacteria identified in this study could help researchers in the meantime discover how to treat infections caused by antibiotic-resistant bacteria by manipulating bile acid.

“A unique cohort, international collaboration, computational analysis, and experimental microbiology all enabled this discovery that the gut microbiome holds the keys to healthy aging,” said co-first author Xavier, core institute member at the Broad. “Our collaborative work shows that future studies focusing on microbial enzymes and metabolites can potentially help us identify starting points for therapeutics.”

Source: Broad Institute of MIT and Harvard

Journal information: Sato Y, Atarashi K, et al. Unique bile acid-metabolizing bacteria in centenarians’ microbiome. Nature. Online July 29, 2021. DOI:10.1038/s41586-021-03832-5