Tag Archives: C difficile research and development

Facile Therapeutics of Belmont, California, To Develop a New Oral Drug for Recurrent Clostridioides difficile Infections

CARB-X today announced an award of up to $1.26 million to  Facile Therapeutics of Belmont, California, to develop a new oral drug for recurrent Clostridioides difficile infections.Facile Therapeutics of Belmont, California, to develop a new oral drug for recurrent Clostridioides difficile infections.

The money will help fund preclinical development of Ebselen, a small-molecule anti-toxin that inhibits a key biochemical function of C difficile toxins A and B, which attack the lining of the intestine. Previous studies showed Ebselen provided protection against severe intestinal damage in mice after they were exposed to virulent C difficile infections. The drug has also been tested in humans in clinical trials for stroke, and although it was not approved for that indication, it was shown to be safe.

“This is a terrific example of an attempt to repurpose a compound for use in the infectious-disease arena,” CARB-X chief of research and development Erin Duffy, PhD, said in a press release. “If successful and ultimately approved for use in patients, Facile’s project could represent tremendous progress in the prevention of recurrent C. difficile infections, and save many lives.”

C difficile infections are traditionally treated with antibiotics, which can cure the infection but also further disrupt the microbiome and clear a path for C difficile bacteria to spread, leading to recurrent infections. At least 20% of patients who get an initial C difficile infection have a recurrent infection.

Facile could receive an additional $17 million if the project achieves certain milestones.

Since its launch in 2016, CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) has awarded more than $222 million to companies developing new treatments and diagnostics for drug-resistant pathogens.
May 18 CARB-X press release

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

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.

 

 

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

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