Tag Archives: C. diff. Research Community

Biologists Develop Models to Aid Development of Novel Therapies to Fight Clostridioides difficile (C. diff.) Pathogen

The Clostridium difficile pathogen takes its name from the French word for “difficult.” A bacterium that is known to cause symptoms ranging from diarrhea to life-threatening colon damage,

 

 

 

C. difficile is part of a growing epidemic of concern for the elderly and patients on antibiotics.

Outbreaks of C. difficile-infected cases have progressively increased in Western countries, with 29,000 reported deaths per year in the United States alone.

Now, biologists at the University of California San Diego are drawing parallels from newly developed models of the common fruit fly to help lay the foundation for novel therapies to fight the pathogen’s spread. Their report is published in the journal iScience.

C. difficile infections pose a serious risk to hospitalized patients,” said Ethan Bier, a distinguished professor in the Division of Biological Sciences and science director of the UC San Diego unit of the Tata Institute for Genetics and Society (TIGS). “This research opens a new avenue for understanding how this pathogen gains an advantage over other beneficial bacteria in the human microbiome through its production of toxic factors. Such knowledge could aid in devising strategies to contain this pathogen and reduce the great suffering it causes.”

As with most bacterial pathogens, C. difficile secretes toxins that enter host cells, disrupt key signaling pathways and weaken the host’s normal defense mechanisms. The most potent strains of C. difficile unleash a two-component toxin that triggers a string of complex cellular responses, culminating in the formation of long membrane protrusions that allow the bacteria to attach more effectively to host cells.

UC San Diego scientists in Bier’s lab-created strains of fruit flies that are capable of expressing the active component of this toxin, known as “CDTa.” The strains allowed them to study the elaborate mechanisms underlying CDTa toxicity in a live model system focused on the gut, which is key since the digestive system of these small flies is surprisingly similar to that of humans.

“The fly gut provides a rapid and surprisingly accurate model for the human intestine, which is the site of infection by C. difficile,” said Bier. “The vast array of sophisticated genetic tools in flies can identify new mechanisms for how toxic factors produced by bacteria disrupt cellular processes and molecular pathways. Such discoveries, once validated in a mammalian system or human cells, can lead to novel treatments for preventing or reducing the severity of C. difficile infections.”

The fruit fly model gave the researchers a clear path to examine genetic interactions disrupted at the hands of CDTa. They ultimately found that the toxin induces a collapse of networks that are essential for nutrient absorption. As a result, the model flies’ body weight, fecal output and overall lifespan were severely reduced, mimicking symptoms in human C. difficile-infected patients.

In addition to Bier, study coauthors include first-author Ruth Schwartz, Annabel Guichard, Nathalie Franc, and Sitara Roy.

The National Institutes of Health (R01 AI110713) funded the research.


Story Source:

Materials provided by the University of California – San Diego. Original written by Mario Aguilera. Note: Content may be edited for style and length.


Journal Reference:

  1. Ruth Schwartz, Annabel Guichard, Nathalie C. Franc, Sitara Roy, Ethan Bier. A Drosophila Model for Clostridium difficile Toxin CDT Reveals Interactions with Multiple Effector Pathways. iScience, 2020; 100865 DOI: 10.1016/j.isci.2020.100865

Transgenic fruit flies help scientists trace the cascade of symptoms caused by toxic infection

Date: February 7, 2020

Source: University of California – San Diego
Summary: Clostridium difficile, a bacterium is known to cause symptoms from diarrhea to life-threatening colon damage, is part of a growing epidemic for the elderly and hospitalized patients. Biologists have now developed models of the common fruit fly to help develop novel therapies to fight the pathogen

Researchers Report Bezlotoxumab Treatment Reduced C. diff. Recurrence in Cancer Patients

Abstract

Background

The incidence of Clostridioides difficile infection (CDI) is reportedly higher and the cure rate lower in individuals with cancer versus those without cancer. An exploratory post-hoc analysis of the MODIFY I/II trials (NCT01241552/NCT01513239) investigated how bezlotoxumab affected the rate of CDI-related outcomes in participants with cancer.

Methods

Participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI antibacterial treatment. A post-hoc analysis of CDI-related outcomes was conducted in subgroups of MODIFY I/II participants with and without cancer.

Results

Of 1,554 participants in the modified intent-to-treat (mITT) population, 382 (24.6%) were diagnosed with cancer (bezlotoxumab 190, placebo 192). Of participants without cancer, 591 and 581 received bezlotoxumab and placebo, respectively. In the placebo group, initial clinical cure (ICC) was achieved by fewer cancer participants versus participants without cancer (71.9% versus 83.1%; absolute difference [95% CI]: -11.3% [-18.6, -4.5]), however, CDI recurrence (rCDI) rates were similar in cancer (30.4%) and non-cancer (34.0%) participants. In participants with cancer, bezlotoxumab treatment had no effect on ICC rate compared with placebo (76.8% versus 71.9%), but resulted in a statistically significant reduction in rCDI versus placebo (17.8% versus 30.4%; absolute difference [95% CI]: 12.6% [-22.5, -2.7]).

Conclusions

In this post-hoc analysis of participants with cancer enrolled in MODIFY I/II, the rate of rCDI in bezlotoxumab-treated participants was lower than in placebo-treated participants. Additional studies are needed to confirm these results.

Open Forum Infectious Diseases, ofaa038, https://doi.org/10.1093/ofid/ofaa038
Published:
31 January 2020

 

To access the article in its entirety please click on the following link:

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofaa038/5718256

Researchers From North Carolina State University Find That Antibiotics Give C.diff. Nutrient-Rich Environment

Using a mouse model, researchers from North Carolina State University have found that antibiotic use creates a “banquet” for Clostridium difficile (C. diff), by altering the native gut bacteria that would normally compete with C. diff for nutrients. The findings could lead to the development of probiotics and other strategies for preventing C. diff infection.

C. diff is a harmful bacterium that can cause severe, recurrent and sometimes fatal infections in the gut. Although the bacteria are commonly found throughout our environment, C. diff infections primarily occur in patients who are taking, or who have recently finished taking, antibiotics.

“We know that antibiotics are major risk factors for C. diff infection because they alter the gut microbiota, or composition of bacteria in the gut, by eliminating the bacteria that are normally there,” says Casey Theriot, assistant professor of infectious disease at NC State and corresponding author of a paper describing the research. “Our latest work suggests that the microbiota may provide natural resistance to C. diff colonization by competing with C. diff for nutrients in that environment; specifically, for an amino acid called proline.”

Theriot and postdoctoral fellow Joshua Fletcher introduced C. diff to antibiotic-treated mice and monitored their gut environment at four intervals: 0, 12, 24, and 30 hours after introduction. They conducted metabolomic and RNA sequencing analysis of the gut contents and the C. diff at these time points to find out which nutrients the bacteria were “eating.” Metabolomics allowed the team to trace the abundance of the nutrients in the gut, and RNA analysis indicated which genes in the C. diff were active in metabolizing nutrients.

The researchers found that the amount of proline in the gut decreased as the population of C. diff increased. Additionally, the amount of a proline byproduct called 5-aminovalerate also increased, indicating that C. diff was metabolizing the proline. The RNA analysis further confirmed C. diff‘s use of proline, as genes related to proline metabolism in C. diff increased during the early stages of colonization, when proline was abundant.

“We’ve been able to show that in the absence of competition C. diff is metabolizing proline and other amino acids in the mouse model, using it as fuel to survive and thrive,” Theriot says. “Hopefully this information could lead to the development of better probiotics, or ‘good’ bacteria that can outcompete C. diff for nutrients in the gut. The ultimate goal is to control these bacteria in ways that don’t rely solely on antibiotics.”

To review article in its entirety please click on the following link to be redirected:

https://www.sciencedaily.com/releases/2018/03/180328204122.htm

Norman B. Javitt, M.D. Is Welcomed As a Member Of the C Diff Foundation, R & D Committee

We are pleased to welcome
Norman B. Javitt, M.D. to the
C Diff Foundation.

Dr. Javitt has an extensive professional career in health care.  New York University Medical Center: Instructor, then Assistant Professor Medicine where his career was devoted mostly to research in liver disease, specifically in inborn errors of cholesterol metabolism affecting newborns, and to teaching medical students.

Cornell University Medical School-New York Hospital:  Associate Professor of Medicine, then Professor of medicine and Chief, Division of Gastroenterology the research program continued to grow, attracting many fellows from all over the world.  Also provided care for private patients, both children and adults, with difficult liver problems.

New York University Medical Center:  Professor of Medicine and of Pediatrics, Division chairman Hepatic Diseases April, Research professor 2015-presnt.  At NYUMC Dr. Javitt has been focusing on C. difficile research  and teaching medical students and house staff.  His research interest has also expand to many areas of cholesterol synthesis and metabolism other than just liver disease.

Dr. Javitt has published research papers in age-related macular degeneration, in vitro fertilization, and Alzheimer’s disease.  He has also published more than 150 research papers, in addition to several books and review articles, and presented work at numerous professional meetings and symposia throughout the world.  His work has been supported by the National Institutes of Health, by private foundations and Pharmaceutical companies.  Dr. Javitt is welcomed by fellow researchers in the Research and Development Committee Chaired by Professor Simon M. Cutting, Ph.D…

Vitality Biopharma Researchers Unlock the Use of Cannabinoid Compounds For the Treatment of Microbes Including Clostridium difficile

Vitality Biopharma a corporation dedicated to the development of cannabinoid prodrug pharmaceuticals, and to unlocking the power of cannabinoids for the treatment of serious neurological and inflammatory disorders, today announced that it has obtained positive results demonstrating antimicrobial activity of cannabinoids and filed for patent protection on the use of cannabinoid compounds for the treatment of microbes including Clostridium difficile and other “superbug” pathogens.

Utilizing a list of the top drug-resistant pathogens from the United States Centers for Disease Control and Prevention (CDC), Vitality researchers screened for antimicrobial activity in their portfolio of compounds. Vitality Biopharma discovered new antimicrobial activities for cannabinoids, and as a result has filed for patent protection on the use of cannabinoids and cannabinoid prodrugs for the treatment of multiple pathogenic bacterial infections.

At the top of the CDC’s list is Clostridium difficile (C. diff), which is classified as an urgent threat to human health. The CDC reported in 2015 that it infected almost 500,000 Americans and was directly responsible for 15,000 deaths. Vitality successfully demonstrated antimicrobial reactivity of a cannabinoid against C. diff, and is currently conducting follow-on studies designed to enable pharmaceutical use of their targeted cannabinoid prodrugs for this application.

The Company also confirmed that cannabinoids have antimicrobial activity towards methicillin-resistant Staphylococcus aureus (MRSA), a pathogen that was recently listed on the World Health Organization’s (WHO) list of priority pathogens that pose a significant threat to human health globally. Additional antimicrobial activity was seen towards other antibiotic-resistant bacterial species that were included on the CDC and WHO lists, and Vitality is seeking broad intellectual property coverage for use of cannabinoids against these pathogens as well.

“Our cannaboside prodrugs enable the targeted delivery of cannabinoids into the large intestine, where C.diff infections colonize, take over, and can cause severe damage.  Our compounds are uniquely suited for performing this task, and it’s now clear they may provide benefits to gut health through multiple mechanisms.” said Dr. Brandon Zipp, Director of R&D at Vitality.  Robert Brooke, the Company’s CEO, adds that, “This is a logical extension of our work that has been focused on gastrointestinal disease, and represents a new opportunity to treat a serious and life-threatening condition.”

 

To read the article in its entirety, click on the link below:

http://www.dddmag.com/news/2017/05/vitality-biopharma-announces-positive-results-cannabinoid-antibiotics

Clostridium difficile Research Suggests That Positively Selected Sites In the Surface Layer Proteins May Play A Role In Driving the Emergence of Hyper-virulent Strains

  • Mark Lynch,
  • Thomas A. Walsh,
  • Izabela Marszalowska,
  • Andrew E. Webb,
  • Micheál MacAogain,
  • Thomas R. Rogers,
  • Henry Windle,
  • Dermot Kelleher,
  • Mary J. O’ConnellEmail author and
  • Christine E. Loscher

To Read Abstract/Article In Its Entirety Please Click On the Following Link:

https://bmcevolbiol.biomedcentral.com/articles/10.1186/s12862-017-0937-8

 

Abstract

Background

Clostridium difficile is a nosocomial pathogen prevalent in hospitals worldwide and increasingly common in the community.

Sequence differences have been shown to be present in the Surface Layer Proteins (SLPs) from different C. difficile ribotypes (RT) however whether these differences influence severity of infection is still not clear.

Results

We used a molecular evolutionary approach to analyse SLPs from twenty-six C. difficile RTs representing different slpA sequences. We demonstrate that SLPs from RT 027 and 078 exhibit evidence of positive selection (PS).

We compared the effect of these SLPs to those purified from RT 001 and 014, which did not exhibit PS, and demonstrate that the presence of sites under positive selection correlates with ability to activate macrophages.

SLPs from RTs 027 and 078 induced a more potent response in macrophages, with increased levels of IL-6, IL-12p40, IL-10, MIP-1α, MIP-2 production relative to RT 001 and 014. Furthermore, RTs 027 and 078 induced higher expression of CD40, CD80 and MHC II on macrophages with decreased ability to phagocytose relative to LPS.

Conclusions

These results tightly link sequence differences in C. difficile SLPs to disease susceptibility and severity, and suggest that positively selected sites in the SLPs may play a role in driving the emergence of hyper-virulent strains.