Ancient Chinese medicine for malaria could potentially aid in treatment of tuberculosis

In continuation of my update on Artemisinin

A centuries-old herbal medicine, discovered by Chinese scientists and used to effectively treat malaria, has been found to potentially aid in the treatment of tuberculosis and may slow the evolution of drug resistance.

In a promising study led by Robert Abramovitch, a Michigan State University microbiologist and TB expert, the ancient remedy artemisinin stopped the ability of TB-causing bacteria, known as Mycobacterium tuberculosis, to become dormant. This stage of the disease often makes the use of antibiotics ineffective.

The study is published in the journal Nature Chemical Biology.

"When TB bacteria are dormant, they become highly tolerant to antibiotics," Abramovitch said, an assistant professor in the College of Veterinary Medicine. "Blocking dormancy makes the TB bacteria more sensitive to these drugs and could shorten treatment times."

One-third of the world's population is infected with TB and the disease killed 1.8 million people in 2015, according to the Centers for Disease Control and Prevention.

Mycobacterium tuberculosis, or Mtb, needs oxygen to thrive in the body. The immune system starves this bacterium of oxygen to control the infection. Abramovitch and his team found that artemisinin attacks a molecule called heme, which is found in the Mtb oxygen sensor. By disrupting this sensor and essentially turning it off, the artemisinin stopped the disease's ability to sense how much oxygen it was getting.

"When the Mtb is starved of oxygen, it goes into a dormant state, which protects it from the stress of low-oxygen environments," Abramovitch said. "If Mtb can't sense low oxygen, then it can't become dormant and will die."

Abramovitch indicated that dormant TB can remain inactive for decades in the body. But if the immune system weakens at some point, it can wake back up and spread. Whether it wakes up or stays 'asleep' though, he said TB can take up to six months to treat and is one of the main reasons the disease is so difficult to control.

"Patients often don't stick to the treatment regimen because of the length of time it takes to cure the disease," he said. "Incomplete therapy plays an important role in the evolution and spread of multi-drug resistant TB strains."

He said the research could be key to shortening the course of therapy because it can clear out the dormant, hard-to-kill bacteria. This could lead to improving patient outcomes and slowing the evolution of drug-resistant TB.

After screening 540,000 different compounds, Abramovitch also found five other possible chemical inhibitors that target the Mtb oxygen sensor in various ways and could be effective in treatment as well.

"Two billion people worldwide are infected with Mtb," Abramovitch said. "TB is a global problem that requires new tools to slow its spread and overcome drug resistance. This new method of targeting dormant bacteria is exciting because it shows us a new way to kill it."

Ref : http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2259.html

Diospyrin inactivates a drug target for tuberculosis in new way

A compound from the South African toothbrush tree inactivates a drug target for tuberculosis in a previously unseen way. 

The compound under research, diospyrin (see below structure), binds to a novel site on a well-known enzyme, called DNA gyrase, and inactivates the enzyme. DNA gyrase is essential for bacteria and plants but is not present in animals or humans. It is established as an effective and safe drug target for antibiotics.

"The way that diospyrin works helps to explain why it is effective against drug-sensitive and drug-resistant strains of tuberculosis," said Professor Tony Maxwell from the John Innes Centre.

In traditional medicine the antibacterial properties of the tree are used for oral health and to treat medical complaints such bronchitis, pleurisy and venereal disease. Twigs from the tree are traditionally used as toothbrushes.

Most antibiotics originate from naturals sources, such as the soil bacteria Streptomyces. Antibiotics derived from plants are less common, but they are potentially rich sources of new medicines.

"Extracts from plants used in traditional medicine provide a source for novel compounds that may have antibacterial properties, which may then be developed as antibiotics," said Professor Maxwell.

Diospyrin inactivates a drug target for tuberculosis in new way

Self-Poisoning of Mycobacterium tuberculosis by targeting GlgE in an a-glucan pathway...

In the past few years, extremely drug resistant strains of TB have arisen that can’t be eliminated by any drugs, so new strategies for attacking TB are urgently needed.

Now, researchers at Albert Einstein College of Medicine of Yeshiva University have found two novel ways of killing the bacteria that cause tuberculosis.

In searching for a new Achilles’ heel for M. tuberculosis, Dr. Jacobs and colleagues focused on an enzyme called GlgE. Previous research had suggested  that GlgE might be essential for the growth of TB bacteria.        (building polysaccharides) GlgE would also be an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut.

Using genetic and biochemical approaches, William Jacobs and colleagues identified four enzymes involved in a pathway that converts a naturally-occurring sugar compound into polysaccharides called alpha-glucans. The scientists found that inactivating one of these enzymes, TreS, was not lethal to the bacteria, indicating that this pathway is not required for growth. 

However, inactivating GlgE was lethal, causing the buildup of toxic levels of the enzyme's sugar substrate, maltose-1-phosphate. In addition, the scientists found that the combined inactivation of TreS and an enzyme for an alternate alpha-glucan biosynthetic pathway was lethal, highlighting the important roles of alpha-glucan's in M. tuberculosis growth.

Sure enough, when the researchers inhibited GlgE, the bacteria underwent "suicidal self-poisoning": a sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.

The researchers discovered a second way of killing TB after observing a crucial connection between their novel alpha glucan pathway and a second pathway that also synthesizes alpha glucans. 

When the researchers knocked out one of the other enzymes in their novel pathway, the pathway's shutdown didn't kill the bacteria; similarly, inactivating an enzyme called Rv3032 in the second alpha glucan pathway failed to kill the microbes. But inactivating both of those enzymes caused what the researchers term synthetic lethality: two inactivations that separately were nonlethal but together cause bacterial death. 

Though the biological role of the GlgE pathway remains to be elucidated, GlgE and the alpha-glucan pathways more generally, are possible drug targets that can now be tested in in vivo models of tuberculosis infection....

"The bacteria that cause TB need to synthesize alpha glucans," notes Dr. Jacobs. "And from the bacterial point of view, you can't knock out both of these alpha glucan pathways simultaneously or you're dead. So if we were to make drugs against GlgE and Rv3032, the combination would be extremely potent. And since TB bacteria need both of those alpha glucan pathways to live, it's very unlikely that this combination therapy would leave behind surviving bacteria that could develop into resistant strains."

Ref :  http://www.nature.com/nchembio/journal/vaop/ncurrent/pdf/nchembio.340.pdf

Tuberculosis can evade immune response !

As I have mentioned in my earlier blog, more than two million people worldwide die from tuberculosis infection every year. Due in part to inappropriate antibiotic usage, there are a rising number (0.5 million in 2007) of cases of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) tuberculosis. New therapies are needed to treat these dangerous infections. We are aware that immune responses to tuberculosis rarely result in complete eradication of the infection. Instead, TB-infected immune cells promote the generation of chronic inflammation and the formation of granulomas, which are areas where the bacteria are contained but not destroyed. These are the facts that encoucouraged Dr. Susanna Grundstrom Brighenti at the Karolinska Institutet in Stockholm, Sweden, to examine the immune response in patients infected with tuberculosis. And this research is of great significance, since it is the first of its kind. The findings are really interesting and justify why the bacterium is getting resistance to the drugs. Following are the important conclusions by the researchers:

The immune cells responsible for killing the tuberculosis bacteria surrounded the granuloma, these cells had low levels of the molecules necessary to kill the TB. Instead, granulomas had high numbers of regulatory immune cells. These regulatory cells suppress the immune response, resulting in the survival of the tuberculosis bacteria and perhaps contributing to persistent long-term infection. Compartmentalization of the immune response in human TB could be part of the reason why infection is never completely eradicated but instead develops into a chronic disease. Congrats for the interesting findings and wish them further success in their future research...

UT Southwestern researchers find clues to TB drug resistance.....

In continuation of my update on TB and its challenges...

Now researchers from the University of Texas Southwestern Medical Center at Dallas, have come up with some interesting info. i.e.,  a type of blood pressure medication shows promise at overcoming some drug-resistant tuberculosis, at least in the laboratory. 

Dr. Gumbo (lead researcher) and his colleagues used an experimental apparatus to simulate the way TB bacteria grow in the human lung. When they exposed the bacteria to drugs commonly used to treat the disease (ethambutol and isoniazid),  the bacterial cells activated a cellular mechanism that pumps each drug out of the cells. 

"The pumping action enables the rapid emergence of high-level resistance to the drugs whether administered together as well as individually, Dr. Gumbo said".

As per the claim by the researchers, resistance was drastically reduced  when the researchers gave the blood-pressure drug reserpine – which is known to block this pumping action – to the TB cells before administering ethambutol and isoniazid.

Researchers now want to test all the first-line drug treatments together with the pump blocker in humans. Hope they will come up with positive results.....

Ref  : http://www.utsouthwestern.edu/utsw/cda/dept37389/files/582308.html

Stroke drug kills bacteria that cause ulcers and tuberculosis

Now researchers  found that, a compound called ebselen (see structure) effectively inhibits the thioredoxin reductase system in a wide variety of bacteria, including Helicobacter pylori which causes gastric ulcers and Mycobacterium tuberculosis which causes tuberculosis. Thioredoxin and thioredoxin reductase proteins are essential for bacteria to make new DNA, and protect them against oxidative stress caused by the immune system. Targeting this system with ebselen, and others compounds like it, represents a new approach toward eradicating these bacteria.

Building on previous observations where ebselen has shown antibacterial properties against some bacteria, Holmgren and colleagues hypothesized that the bacteria sensitive to ebselen relied solely on thioredoxin and thioredoxin reductase for essential cellular processes. They investigated this by testing it on strains of E. coli with deletions in the genes for thioredoxin, thioredoxin reductase and the glutaredoxin system. They found that strains with deletions in the genes coding for glutaredoxin system were much more sensitive than normal bacteria. Researchers further tested ebselen againstHelicobacter pylori andMycobacterium tuberculosis, which both naturally lack the glutaredoxin system and are frequently resistant to many commonly used antibiotics, and found both to be sensitive to ebselen.

"As rapidly as these organisms evolve, we need new drugs sooner rather than later," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "The fact that these scientists have found a new target for killing some of the most resistant bacteria is great news, but the fact that we already have at least one drug which we could possibly use now makes the news even better."

Ref : http://www.fasebj.org/content/early/2012/12/17/fj.12-223305

Stroke drug kills bacteria that cause ulcers and tuberculosis

Novel iron complexes (quinoxaline) as potential antitubercular agents...

A team of researchers from Spain and Latin America have synthesized two iron compounds(complex with qunoxaline derivative below structure)  that inhibit the in vitro growth of Mycobacterium tuberculosis, the bacteria that causes tuberculosis. Due their low level of toxicity in mammel cells, the compounds could be used in the future as therapeutic agents and hospital disinfectants.  

As per the claim by the researchers, the complexes are better than the second line drugs (we know already about drug resistant tubercular species and tuberculosis is being considered as re-emerging disease due to the increase in the number of people with HIV and other viruses that attack the immune system, as well as to the increasing consumption of immunosuppressive and recreational drugs).  Another advantage of the iron compounds is that they show low toxicity in mammal cells, as demonstrated by the experiments performed with mice cells.

"That is why these compounds are useful as hospital disinfectants or therapeutic agents," the Uruguayan researchers highlight, albeit recalling that, at present, they in vitro trials "and the line of research remains open to learn more about how they act."

Researchers conclude that, the novel complexes showed in vitro growth inhibitory activity on Mycobacterium tuberculosis H₃₇Rv (ATCC 27294), together with very low unspecific cytotoxicity on eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M. tuberculosis than the “second-line” therapeutic drugs....

Ref : Dinorah Gambino et.al., Journal of Inorganic Biochemistry Volume 104, Issue 11

New treatment kills off infection that can be deadly to cystic fibrosis patients

A new treatment developed by researchers at Aston University and Birmingham Children's Hospital has been found to completely kill a bacterial infection that can be deadly to cystic fibrosis patients and other chronic lung conditions such as bronchiectasis.

The findings, which are published in the journal Scientific Reports, show that scientists from Aston University, Mycobacterial Research Group, combined doses of three antibiotics—amoxicillin and imipenem-relebactam and found it was 100% effective in killing off the infection which is usually extremely difficult to treat in patients with cystic fibrosis. The infection results in severe decline in lung function and sometimes death.

                                

amoxicillin                                                                   Imipenem  \

 Relebactam

Cystic fibrosis (CF) is a genetic condition affecting more than 10,000 people in the UK (Cystic Fibrosis Trust) and there are more than 70,000 people with the condition worldwide (Cystic Fibrosis Foundation). While bronchiectasis affects 210,000 people in the UK (British Lung Foundation).

Mycobacterium abscessus is a bacterial pathogen from the same family that causes tuberculosis, which causes serious lung infections in people (particularly children) with lung disorders, most notably cystic fibrosis. It is highly drug resistant. Currently patients are given a cocktail of antibiotics that cause serious side effects including severe hearing loss and often doesn't result in cure.

The researchers used samples of the pathogen taken from 16 infected cystic fibrosis patients and tested the new drug combination to discover how much was required to kill the bacteria. They found the amounts of amoxicillin-imipenem-relebactam required were low enough to be given safely to patients.

Until now Mycobacterium abscessus has been virtually impossible to eradicate in people with cystic fibrosis. It can also be deadly if the patient requires a lung transplant because they are not eligible for surgery if the infection is present.

In the UK, of the 10,000 people living with cystic fibrosis, Mycobacterium abscessus infects 13% of all patients with the condition. This new treatment is advantageous not only because it kills off the infection, but it does not have any side-effects on patients, thus ensuring their quality of life and greatly improving survival chances for infected CF patients.

Dr. Jonathan Cox, Lecturer in Microbiology, Aston University and leader of the team that discovered this new treatment said: "This new drug combination is a significant step forward for patients with cystic fibrosis that get infected with the deadly Mycobacterium abscessus bacteria. Our new drug combination is significantly less toxic than those currently used, and so far we have managed to kill every patient's bacterial isolate that we have received.

"This shows our drugs, when used in combination, are widely effective and could therefore make a huge difference to people whose treatment options are currently limited.

"Because amoxicillin is already widely available and imipenem-relebactam has just been approved for use by the Food and Drug Administration (FDA) in the US, these drugs are already available to clinicians. We therefore hope to start treating patients as soon as possible. "

The findings of this research will impact children being treated for the infection at Birmingham Children's Hospital—who part funded the research—but it can also be used nationally and further afield.

With more funding, the next stage of the research will be to test the treatment on more people with CF infected by this bacterium, comparing it to the antibiotics that are currently used.

Dr. Maya Desai, Consultant in Respiratory Paediatrics, Birmingham Children's Hospital added: "This exciting development will significantly impact on the care of CF patients globally. It has been possible only with close collaboration between Aston University and Birmingham Children's Hospital both from a clinical research and financial point of view."

Dr. Paula Sommer, Head of Research at the Cystic Fibrosis Trust said: "It's exciting that these lab-based studies investigating new antibiotic treatments for M. abscessus infection are showing such promise and adding to our expanding knowledge of this devastating bug.

"Mycobacterium abscessus also known as NTM, is the most feared infection a person with cystic fibrosis can develop. Taking drugs to treat NTM can add to an already significant regime of daily treatments and take up to a year to clear infections. We look forward to a time when effective, short courses of treatment are available to treat NTM."

https://en.wikipedia.org/wiki/Amoxicillin

https://en.wikipedia.org/wiki/Imipenem                                                                                                      https://en.wikipedia.org/wiki/Relebactam

https://medicalxpress.com/news/2019-10-fda-drug-common-cystic-fibrosis.html

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

 TB Alliance’s new drug application (NDA) for the novel tuberculosis (TB) drug candidate pretomanid has been accepted for review by the United States Food and Drug Administration (FDA). The application is for the use of pretomanid as part of a new regimen, in combination with bedaquiline and linezolid, for the treatment of extensively drug-resistant (XDR) TB, treatment intolerant multidrug-resistant (MDR) TB, and treatment non-responsive MDR-TB.

The NDA for pretomanid has been granted Priority Review by FDA. The Prescription Drug User Fee Act (PDUFA) action date for an FDA decision is in third quarter 2019.

TB Alliance will work with manufacturing partners to ensure that pretomanid, if approved for use in the BPaL regimen, will be accessible to those who need it.

About Pretomanid and the BPaL Regimen

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. It has been studied in 20 clinical trials alone or in combination with other anti-TB drugs. Since TB Alliance began development of pretomanid in 2002, it has been administered in a clinical trial setting to more than 1,200 people in 14 countries.

The BPaL regimen (comprised of bedaquiline, pretomanid and linezolid) was first studied clinically in the Phase 3 Nix-TB trial. Nix-TB participants with XDR-TB and treatment intolerant or nonresponsive MDR-TB were enrolled for treatment with the BPaL regimen for six months, extendable to nine months, with the intent to cure. Nix-TB is an open label, single arm trial. According to a modified intention-to-treat analysis of interim results on the first 75 participants presented at the 2018 Union World Conference on Lung Health, 89% of the trial participants had a favorable outcome with their clinical infection resolved and sputum cultures negative for TB after six months of treatment and six months of post-treatment follow-up.

https://www.tballiance.org/portfolio/compound/pretomanid

https://en.wikipedia.org/wiki/Pretomanid

https://www.drugbank.ca/drugs/DB05154

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

A new avenue for TB therapy !

TB bacteria actually sends signals that encourage the growth of those organized granuloma structures, and for good reason: each granuloma serves as a kind of hub for the infectious bugs in the early stages of infection, allowing them to expand further and spread throughout the body. Which is something interesting in he sense that the earlier believed fact (i.e., masses of immune cells that form as a hallmark of tuberculosis (TB) have long been thought to be the body's way of trying to protect itself by literally walling off the bacteria) is being ruled out?. Scientists thought they were protective, but they are not - at least not in early infection. The bacteria use them to reproduce and disseminate themselves.
Not only do the bacteria expand themselves within the first granuloma to form, she added, but some of the immune cells in that initial mass leave to start new granulomas elsewhere. Those new granulomas then also serve as breeding grounds for the bacteria. The finding (Lalita Ramakrishnan and J.Davis). suggests a new avenue for TB therapy at an important time in the struggle against TB infection (not only the increasing number of patients, AIDS with TB and drug resistant TB). So if one can prevent granulomas that might be therapeutic either by intercepting the bacterial signal that spurs granulomas' formation or by manipulating the human immune system in some other way. Hope this research will go a long way in finding the solution to the epidemic drug resistant TB........

FDA Grants Soligenix “Fast Track” Designation for SGX943 for the Treatment of Melioidosis

Soligenix, Inc. (Soligenix or the Company), a late-stage biopharmaceutical company focused on developing and commercializing products to treat rare diseases where there is an unmet medical need, announced today that its SGX943 (dusquetide) development program has received “Fast Track” designation from the US Food and Drug Administration (FDA) as adjunctive therapy with other antibacterial drugs, for the treatment of melioidosis, a serious and potentially life-threatening condition.

 SGX943 (dusquetide)

Fast track is a designation that the FDA reserves for a drug intended to treat a serious or life- threatening condition and one that demonstrates the potential to address an unmet medical need for the condition. Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, should events warrant, Soligenix will be eligible to submit a new drug application (NDA) for SGX943 on a rolling basis, permitting the FDA to review sections of the NDA prior to receiving the complete submission. Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately six months.

“We are very pleased to have been granted fast track designation from the FDA,” stated Christopher J. Schaber, PhD, President and Chief Executive Officer of Soligenix. “We believe that the FDA’s action in granting fast track designation validates the unmet medical need that currently exists for the treatment of melioidosis and for the potential key role SGX943 can serve as a therapy in this rare, life-threatening disease. We look forward to working with the federal government to advance this biodefense development program.”

About Melioidosis

Melioidosis is a potentially fatal infection caused by the Gram-negative bacillus, Burkholderia pseudomallei(Bps). Highly resistant to many antibiotics, Bps can cause an acute disease characterized by a fulminant pneumonia and a chronic condition that can recrudesce. There is no preventive vaccine or effective immunotherapy for melioidosis. Therefore, there is a significant medical need for improved prevention and therapy.

Bps and the closely related Burkholderia mallei (Bm) are considered possible biological warfare agents by the Department of Health and Human Services (DHHS) because of the potential for widespread dissemination through aerosol. Bps is classified as a Tier 1 biothreat and a category B priority pathogen by the NIAID and is a top 5 priority in the most recent Public Health Emergency Medical Countermeasure Enterprise (PHEMCE) Strategy document.

Bps infection (melioidosis) is a major public health concern in the endemic regions of Southeast Asia and Northern Australia. Moreover, the organism has a worldwide distribution and the full extent of global spread is likely underestimated. Bps activity is seen in Southeast Asia, South America, Africa, the Middle East, India, and Northern Australia. The highest pockets of disease activity occur in Northern Australia and Northeast Thailand, Burma and Vietnam, and is likely under-reported in China. In Northeast Thailand, the mortality rate associated with Bps infection is over 40%, making it the third most common cause of death from infectious disease in that region after HIV/AIDS and tuberculosis.

About SGX943

SGX943 is the drug product designation for the active ingredient dusquetide in the treatment of melioidosis. Dusquetide is an IDR, a new class of short, synthetic peptides that has a novel mechanism of action in that it has simultaneous anti-inflammatory and anti-infective activity. IDRs have no direct antibiotic activity but modulate host responses, increasing survival after infections with a broad range of bacterial Gram-negative and Gram-positive pathogens, as well as accelerating resolution of tissue damage following exposure to a variety of agents including bacterial pathogens, trauma and chemo- and/or radiation-therapy. Dusquetide has demonstrated safety in a Phase 1 clinical study in 84 healthy human volunteers and preliminary efficacy and safety in an exploratory Phase 2 clinical study in 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer. Dusquetide has also previously demonstrated efficacy in numerous animal disease models including melioidosis, mucositis, colitis, skin infection and other bacterial infections. Dusquetide and related analogs have a strong intellectual property position, including composition of matter. Dusquetide was developed pursuant to discoveries made by Professors B. Brett Finlay, PhD and Robert Hancock, PhD of the University of British Columbia.