Tag Archives: C difficile research and development

Clostridium difficile Infection Research and Development Community – Update On Antibody-based Immunotherapies

An update on antibody-based immunotherapies for Clostridium difficile infection

Authors Hussack G, Tanha J

Greg Hussack,1 Jamshid Tanha1–3

1Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, 2School of Environmental Sciences, University of Guelph, Guelph, 3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada

Abstract: Clostridium difficile continues to be one of the most prevalent hospital-acquired bacterial infections in the developed world, despite the recent introduction of a novel and effective antibiotic agent (fidaxomicin). Alternative approaches under investigation to combat the anaerobic Gram-positive bacteria include fecal transplantation therapy, vaccines, and antibody-based immunotherapies. In this review, we catalog the recent advances in antibody-based approaches under development and in the clinic for the treatment of C. difficile infection. By and large, inhibitory antibodies that recognize the primary C. difficile virulence factors, toxin A and toxin B, are the most popular passive immunotherapies under investigation. We provide a detailed summary of the toxin epitopes recognized by various antitoxin antibodies and discuss general trends on toxin inhibition efficacy. In addition, antibodies to other C. difficile targets, such as surface-layer proteins, binary toxin, motility factors, and adherence and colonization factors, are introduced in this review.

Click on the following link to access article in its entirety:

https://www.dovepress.com/an-update-on-antibody-based-immunotherapies-for-clostridium-difficile–peer-reviewed-article-CEG

Researchers Make Chemical Changes In the InsP6 Inhibitor To Improve Its Hydrogen Bonding Capabilities With C. difficile Toxins

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Infections with bacterium Clostridium difficile have rapidly become a significant medical problem in hospitals and long-term care facilities. The bacteria cause diarrhea and life-threatening inflammation of the colon by producing toxins that kill the endothelial cells that form the lining of the gut.

Although a natural inhibitor of these toxins, called InsP6, works in the test tube, it is not very efficient when administered orally.

Traditional methods to optimize InsP6 have until now not been successful, but researchers at Baylor College of Medicine have discovered that changing one atom in InsP6 can increase its ability to neutralize the toxins by 26-fold.

The results appear in Science Advances.

“The toxins, called TcdA and TcdB, are very large molecules that kill the cells very efficiently,” said Dr. Tor Savidge, associate professor of pathology and immunology and of pediatrics, director of the Savidge Lab at the Texas Children’s Microbiome Center and senior author of the paper. “It’s like delivering a warhead into the cell. The toxins bind to the cell and the cell internalizes them in a sack of cell membrane called endosome. Not all of the toxin will exit this sack to kill the cell, just the little warhead pokes its head out. Another section of the toxin senses when the warhead is outside the sack and cleaves it. The warhead is released, interferes with basic functions and kills the cell,” said Savidge.

To neutralize the toxins, the researchers targeted the section that senses when the warhead is inside the cell, called allosteric modulator. “The strategy we have tried is to make the toxin ‘think,’ before it binds to and enters the cell, that the warhead is ready to be released, so it releases it prematurely,” said Savidge. When the warhead is released outside the cell, it is neutralized. InsP6, the toxins’ natural inhibitor, works this way, but is not very efficient.

Finding molecules that would bind to the allosteric modulator and trigger the premature release of the warhead involved analyzing and testing half a million molecules listed in large databases. Dr. Numan Oezguen, a member of the Savidge Lab, used virtual drug screening to sift through the databases to identify candidate molecules that most likely would bind to the allosteric modulator. One of his screening strategies consists of creating virtual 3-D structures of the molecules, projecting them on a large screen and using 3-D glasses to determine the most likely interactions between molecules. The molecules whose virtual analysis suggested they would bind to the allosteric modulator were then tested in the lab.

“We found that allosteric mechanisms are very complicated,” said Savidge. “You can find something that binds and you think, well, this is probably a good candidate for this, but it’s not right. It binds, but it doesn’t trigger the premature release of the warhead.”

Far from discouraging their efforts, the results motivated the researchers to better understand what makes interactions between molecules stronger or weaker. Their comprehensive analysis of numerous molecules provided insights into how water contributes to molecular interactions, in particular those involving hydrogen bonds, one of the most important bonds between molecules. The roles of water and hydrogen bonding had not been considered in this way before.

“When you take water into consideration you need to acknowledge that it can form hydrogen bonds, which may or may not compete or interfere with those formed between other molecules such as C. difficile toxins and their inhibitors, which interact in the gut, surrounded by water,” said Savidge.

“Before we considered the role of water, the predominant idea was that to strengthen the interaction between molecules the ability to form hydrogen bonds had to be made as strong as possible in the drug. It turns out this is not the case,” said Oezguen. Many times drugs designed to be able to make strong hydrogen bonds bind poorly to their targets.

The researchers discovered that to enhance the binding of a drug to its target, both sides of the hydrogen bond, the side on the drug and the one on the target, have to have either significantly stronger or significantly weaker hydrogen bonding capabilities.

On the other hand, a mixed strong-weak hydrogen bond pairing decreases the overall binding of the drug to its target, in some cases by 3 million fold. The decrease in binding is the result, the researchers propose, of water molecules forming hydrogen bonds with the drug and its target, therefore preventing the drug and the target from forming hydrogen bonds between them.

With all this information in hand, the researchers proceeded to make chemical changes in the InsP6 inhibitor to improve its hydrogen bonding capabilities with
C. difficile toxins.

One of the modifications, changing one single atom in InsP6, strengthened InsP6 binding to the allosteric modulator by 26-fold. This observation builds on a report published by Savidge in Science last year exploring the role of water interactions in the origin of enzymatic catalytic power.

Plans are currently underway to exploit these fundamentally new concepts in the precision design of future therapeutic applications.

Other contributors to this work are Deliang Chen, now in Gannan Normal University, China, who contributed conceptual and theoretical proof of the hydrogen bonding pairing principle; Petri Urvil from Baylor performed lab studies; Colin Ferguson from Echelon Biosciences, Inc. synthesized the more efficient inhibitor; and Sara Dann from the University of Texas Medical Branch in Galveston, contributed animal studies.

This work was supported by grants RO1AI100914 and DK56338 from the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, and the National Science Foundation of China (21473041).

Source: https://www.bcm.edu/

 

To read the article in its entirety click on the following link:

http://www.azom.com/news.aspx?newsID=45377

C. diff. Spores and More Global Broadcasting Network Welcomes Guests; Dr. Michael Stecher, Dr. Sushma Shivaswamy, and Mr. Kelly Thornburg of XBiotech

XBiotech will discuss their novel True Human ™ approach on Tuesday, February 2nd at
10 a.m. Pacific Time,,   11 a.m. Mountain Time,
12 p.m. Central Time,    1 p.m. Eastern Time.

on C. diff. Spores and More™”  Global Broadcasting Network – an educational program dedicated to  C. difficile Infections  and more —  brought to you by VoiceAmerica and sponsored by Clorox Healthcare

http://www.voiceamerica.com/show/2441/c-diff-spores-and-more

 

This episode introduces XBiotech, developer of True Human ™ therapeutic antibodies.  XBiotech has an exciting pipeline of product candidates in various areas of medicine.  The Company recently anounced the launch of a research and development program to develop a first-in-class oral monoclonal antibody against Clostridium difficile (C. diff. ) infection.  The Company will discuss the need for an effective C. difficile therapy, their novel approach to treating the infection as well as efficiency in their manufacturing technology.

Join guests Dr. Michael Stecher,MD,  Medical Director, Dr. Sushma Shivaswamy, Ph.D., Vice President of Research and Development and Mr. Kelly Thornburg, Senior Vice President of Operations as they discuss how XBiotech is pioneering a new era in the discovery and development of targeted antibodies therapeutics.

 

XBiotech

 

XBiotiech is rethinking the way medicines are discovered and commercialized– from pioneering ways to create safer drugs that harness our natural immunity to disease, to developing technology that enables rapid transition from discovery to large-scale manufacturing.  “At XBiotech we believe there is vast potential for next generation antibody therapies derived from natural immunity to disease.  We believe our innovation in technology and in the clinic enables us to bring our new discoveries to patients more efficiently than any other bio-pharmaceutical developer in the industry. ”

 

Michael G. DeGroote School of Medicine at McMaster Researchers Discover New Superbug Test With Quick Diagnosis

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McMaster researchers have come up a way for inventing molecule probes to quickly identify deadly bacterial strains of infectious disease.

The find, published as a “hot paper” by a German scientific journal because of its importance, shows promise for detecting specific strains of bacteria and tracking their specific trail of illness.

 

“With this new technology we will be able to develop molecular tools to recognize any superbug down to the specific strain, and there will be many wide-ranging applications,” said Yingfu Li, principal investigator and a professor of biochemistry and biomedical sciences for the Michael G. DeGroote School of Medicine at McMaster.

The scientists have found a way to make DNAzymes, or single-stranded catalytic DNA molecules from a simple test tube technique that allows for isolation of rare DNA sequences with special functions.

The research team’s first success was the development of a that precisely recognizes the strain which caused the 2011 Hamilton, Ont. outbreak of Clostridium difficile infection. This strain was very infectious, resistant to antibiotics and even fatal to some patients. Instead of having to do several different tests to narrow down to a positive identification of the specific strain, the researchers can now quickly pinpoint this superbug using their new molecular probe.

“This sets up the stage for numerous other applications where we can exploit synthetic DNAzyme probes for diagnosing infectious disease,” said Li.

The test can be done in less than an hour, compared to the current 48 hours, allowing for rapid, more accurate treatment of patients.

“This technology can be extended to the further discovery of other superbug strain-specific pathogens.  For example, such technology would prove useful in the identification of hypervirulent or resistant strains, implementation of the most appropriate strain-specific treatments and tracking of outbreaks”, said Bruno Salena, a co-author of the study, an associate professor of medicine for the Michael G. DeGroote School of Medicine and a gastroenterologist with Hamilton Health Sciences.

“This technology is inexpensive, accessible without a lab, and will ultimately be adaptable to identify not just many other bacteria or viruses, but even other diseases,” he said.

Resource:

To read the article in its full version click on the link below:

 

http://m.phys.org/news/2015-12-infectious-disease-quick-diagnosis.html

 

 

“C. diff. Spores and More ™” C diff Radio Returns To Live Broadcasting Tuesday, January 19th

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Welcome to Season 2

C. diff. Spores and More ™”

Join us for live broadcasting  on Tuesday January 19th, 2016 at 10 a.m. Pacific Time,
11 a.m. Mountain Time, 12 p.m. Central Time,   1 p.m. Eastern Time.

 

Programming for Tuesday, January 19th:
“C. difficile Infections; The What, Where and How.”

This episode of “C. diff. Spores and More” is focused on
“C. difficile Infections; The What, Where and How.”
What is it,  What can be done to prevent acquiring it,
Where is it acquired, Where can clinicians and patients
learn more about this infection, How is it being prevented at home
and in the hospitals, How CDI’s are being treated, and How to learn more about the
prevention, treatments, and environmental safety products available
With our special guests:

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Dr. Caterina Oneto,, MD

 

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and Dr. Paul Feuerstadt, MD,
Both professors and physicians specializing in Gastroenterology with
a wealth of knowledge and experience treating patients
with a CDI and through ongoing scientific/medical research.

 

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 Click Image Above to Listen to Archived Shows

 

We are pleased to share  “C. diff. Spores and More ™”  with you because, as advocates
of C. diff., we know the importance of this cutting-edge new weekly radio show
and what it means for our Foundation’s community worldwide.

Hard Facts: Deaths and illnesses are much higher than reports have shown Nearly half a million Americans suffered from Clostridium difficile (C. diff.) infections in a single year according to a study released today, February 25, 2015, by the Centers for Disease Control and Prevention (CDC).

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Previous studies indicate that C. diff. has become the most common
microbial cause of Healthcare-Associated Infections found in U.S. hospitals
driving up costs to $4.8 billion each year in excess health care costs in acute
care facilities alone. Approximately two-thirds of C. diff. infections
were found to be associated with an inpatient stay in a health care facility,
only 24% of the total cases occurred in patients while they were hospitalized.
The study also revealed that almost as many cases occurred in nursing homes as
in hospitals and the remainder of individuals acquired the
Healthcare-Associated infection, C. diff., recently discharged from
a health care facility.

This new study finds that 1 out of every 5 patients with the
Healthcare-Associated Infection (HAI), C. diff., experience
a recurrence of the infection and 1 out of every 9 patients over the
age of 65 diagnosed with a HAI – C. diff. infection died
within 30 days of being diagnosed. Older Americans are quite vulnerable
to this life-threatening diarrhea infection. The CDC study also found
that women and Caucasian individuals are at an increased risk of
acquiring a C. diff. infection.
The CDC Director, Dr. Tom Frieden, MD, MPH said, “C. difficile
infections cause immense suffering and death for thousands of Americans
each year.” “These infections can be prevented by improving antibiotic
prescribing and by improving infection control in the health care system.
CDC hopes to ramp up prevention of this deadly infection by supporting
State Antibiotic Resistance Prevention Programs in all 50 states.”

“This does not include the number of C. diff. infections taking place
and being treated in other countries.”  “The  C Diff Foundation supports hundreds
of communities by sharing the Foundation’s mission and
Raising C. diff. awareness to healthcare professionals,patients,
families,  and communities working towards a shared goal ~  witnessing a
reduction of newly diagnosed C. diff. cases by 2020 .”
” The C Diff Foundation volunteer Advocates are truly appreciated and stand
with the Foundation members creating positive changes through
time and dedication in “Raising C. diff. awareness ™”  worldwide.

C. diff. Spores and More ™“ spotlights world
renowned topic experts, research scientists, healthcare professionals,
organization representatives, C. diff. survivors, board members,
and C Diff Foundation volunteer advocates  – all working together to
create positive changes in the C. diff. community and more.

Through their interviews, the C Diff Foundation mission will
connect, educate, and empower our worldwide listeners.

Do you have Questions?  Email them to the C Diff Foundation at

info@cdifffoundation.org or through the show page portal.
Questions will be addressed  by the show’s Medical Correspondent, Dr. Fred Zar, MD, FACP,
Dr. Fred Zar is a Professor of Clinical Medicine,
Vice HeZarPhotoWebsiteTop (2)ad for Education in the Department of Medicine, and Program Director of the Internal Medicine Residency
at the University of Illinois at Chicago.  Over the last two decades he has
been a pioneer in the study of the treatment of Clostridium difficile disease
and the need to stratify patients by disease severity.

 

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Programming for “C. diff. Spores and More ™”   is made
possible through our official Corporate Sponsor;  Clorox Healthcare™

Click on the Clorox Healthcare Logo to visit their website.

Moving the Dial A Little Closer To Better Treatment and Prevention Of C. diff. Infections

NewsSpeaker

 

 

 

Researchers at Vanderbilt University Medical Center have obtained the crystal structure of a toxin from the bacterium Clostridium difficile (C. diff)   a leading hospital-acquired infection  in the United States.

“This is basic science. I think it gives a framework for understanding how, once you do have an infection, the toxins are causing the disease,” says senior author D. Borden Lacy, PhD, associate professor of Pathology, Microbiology and Immunology and of Biochemistry.

Like anthrax, diphtheria and botulism, C. diff infection is a toxin-mediated disease. The bacterium actually produces two similar toxins, toxin A and toxin B. But unlike the other infections, there is as yet no vaccine or other treatment that can effectively block C. diff toxins.

Meanwhile, C. diff has become a major public health menace. In 2011, the bacterium caused nearly half a million infections in the United States, and approximately 29,000 people died from intestinal complications, including a form of colitis, within a month of the initial diagnosis.

In 2012 and 2013, Lacy and her colleagues reported the mechanism by which toxin B kills cells. Earlier this year, they reported the identification of the cellular receptor that binds the toxin.

After binding to their receptors, the toxins are enveloped by an endosome, or tiny vesicle. Through a pore it drills into the cell membrane, each toxin then sends pieces of itself with two enzymatic activities into the cell. The enzymes modify the activity of cellular proteins, ultimately killing the cell.

In the current study, the researchers, led by Lacy’s research assistant, Stacey Rutherford, generated the crystal structure of C. diff toxin A. Benjamin Spiller, PhD, associate professor of pharmacology and of pathology, microbiology and immunology, also contributed to the crystallography.

At Argonne National Laboratory outside Chicago, the researchers bounced a highly focused X-ray of a specific wavelength off the crystal. The resulting diffraction pattern was then converted using computational methods into a model of the toxin.

They found that one small section of the toxin is “highly conserved,” meaning that its sequence of amino acids is identical to the same sequence in other Clostridium species.

This “suggests that antibodies specific for this conserved region could provide protection against multiple toxin-mediated clostridium infections and points to a generalizable strategy for generating safe vaccine antigens for this class of toxins,” they conclude.

In addition, Nicole Chumbler, a graduate student in the Lacy lab who is now a postdoctoral fellow at Harvard Medical School, found that zinc is bound to the toxin and is required for its activity. Small molecules targeting the zinc-binding enzyme could block the toxin’s effects.

Much remains to be discovered, Lacy says, but each study moves the dial a little closer to better treatment and prevention of C. diff infections.

 

The research was supported in part by National Institutes of Health grants AI095755 and GM042569.

 

Source: Vanderbilt University Medical Center

 

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

 

http://www.infectioncontroltoday.com/news/2016/01/researchers-closer-to-a-better-treatment-for-clostridium-difficile.aspx

 

 

Asymptomatic carriers of toxigenic C. difficile in long-term care

Asymptomatic carriers of toxigenic C. difficile in long-term care facilities: a meta-analysis of prevalence and risk factors.

Abstract

BACKGROUND:

The impact of Clostridium difficile colonization in C. difficile infection (CDI) is inadequately explored. As a result, asymptomatic carriage is not considered in the development of infection control policies and the burden of carrier state in long-term care facilities (LTCFs) is unknown.

PURPOSE:

To explore the epidemiology of C. difficile colonization in LTCFs, identify predisposing factors and describe its impact on healthcare management.

DATA SOURCES:

PubMed, Embase and Web of Science (up to June 2014) without language restriction, complemented by reference lists of eligible studies.

STUDY SELECTION:

All studies providing extractable data on the prevalence of toxigenic C. difficile colonization among asymptomatic residents in LTCFs.

DATA EXTRACTION:

Two authors extracted data independently.

STATISTICAL METHODS:

The pooled colonization estimates were calculated using the double arcsine methodology and reported along with their 95% random-effects confidence intervals (CIs), using DerSimonian-Laird weights. We assessed the impact of patient-level covariates on the risk of colonization and effects were reported as odds ratios (OR, 95% CI). We used the colonization estimates to simulate the effective reproduction number R through a Monte Carlo technique.

RESULTS:

Based on data from 9 eligible studies that met the specified criteria and included 1,371 subjects, we found that 14.8% (95%CI 7.6%-24.0%) of LTCF residents are asymptomatic carriers of toxigenic C. difficile. Colonization estimates were significantly higher in facilities with prior CDI outbreak (30.1% vs. 6.5%, p = 0.01). Patient history of CDI (OR 6.07; 95% CI 2.06-17.88; effect derived from 3 studies), prior hospitalization (OR 2.11; 95% CI 1.08-4.13; derived from 3 studies) and antimicrobial use within previous 3 months (OR 3.68; 95% CI 2.04-6.62; derived from 4 studies) were associated with colonization. The predicted colonization rate at admission was 8.9%.

CONCLUSION:

Asymptomatic carriage of toxigenic C. difficile represents a significant burden in LTCFs and is associated with prior CDI outbreaks in the facility, a history of CDI, prior hospitalization and antimicrobial use. These findings can impact infection control measures at LTCFs.

To read this article/abstract in its entirety click on the link below:

http://www.ncbi.nlm.nih.gov/pubmed/25707002