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.

New drug regimens could significantly improve treatment for tuberculosis

Researchers from UCLA and Shanghai Jiao Tong University have made an important step toward a substantially faster and more effective treatment for tuberculosis, which infects some 10 million people and causes 1.5 million deaths each year.

Combination therapy, which utilizes a series of drugs, is a clinical standard for many major diseases. However, the number of potential combinations of different drugs and dose levels can be in the billions, making the prospect of choosing the best one seem daunting.

The research was published in the Proceedings of the National Academy of Sciences.

In the study, researchers used a technique called feedback system control, which was developed at UCLA, to study cells infected with the bacteria that cause tuberculosis. They quickly narrowed combinations of 14 different tuberculosis drugs with five different doses -- resulting in 6 billion possibilities -- into several promising combination treatments that kill the bacteria that cause tuberculosis much faster than the standard regimen used to treat tuberculosis.

"Designing a drug combination with optimized drug-dose ratios has, until now, been virtually impossible," said Chih-Ming Ho, the study's principal investigator and the Ben Rich-Lockheed Martin Chair Professor at UCLA's Henry Samueli School of Engineering and Applied Science. "Feedback system control technology demonstrated it can pinpoint these best possible ratios for a wide spectrum of diseases."

"If our findings are confirmed in human studies, the new drug regimens that we have identified should dramatically shorten the time needed to treat tuberculosis," said Dr. Marcus Horwitz, a senior author on the research and a distinguished professor of medicine and microbiology, immunology and molecular genetics at the UCLA David Geffen School of Medicine. "This will increase the likelihood of successful treatment and decrease the likelihood of patients developing drug-resistant tuberculosis. A highly successful and rapid treatment may hasten the eventual eradication of tuberculosis."

New drug regimens could significantly improve treatment for tuberculosis: Researchers from UCLA and Shanghai Jiao Tong University have made an important step toward a substantially faster and more effective treatment for tuberculosis, which infects some 10 million people and causes 1.5 million deaths each year.

Scientists identify new agent to combat tuberculosis

(Griselimycin)

Above pic: The protein forms a homodimeric ring (shown as blue cartoon & surface representation). Each polypetide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground).

According to figures of the World Health Organization, some 8.7 million people contracted tuberculosis in 2012 and this disease is fatal for approximately 1.3 million people throughout the world each year. One of the main problems is that the tuberculosis pathogens have become resistant to the antibiotics used to fight them. Scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken, the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the German Center for Infection Research (DZIF) joined forces with scientists from Sanofi, a global health care company, and identified a new agent, which might potentially remedy these problems. The scientists just described this agent and its unique mechanism of action in the highly renowned scientific journal Science.

Mycobacterium tuberculosis is the main cause of tuberculosis. The treatment for drug-susceptible tuberculosis consists of the daily administration of multiple drugs for a minimum of six months. Lack of adherence to this regimen can result in treatment failure and the emergence of drug resistance. "Complexity and duration of the treatment are true issues and the main reasons for the development of resistant pathogens," says Prof Rolf Müller, who is the Executive Director and head of the Microbial Natural Substances department of the HIPS, an institution jointly sponsored by the HZI and Saarland University.

Consequently, there is an urgent need for new medications and therapeutic approaches to both fight the resistant pathogens, as well as to shorten the duration for the treatment of drug-susceptible organisms. Based on earlier reports, Müller, in collaboration with Prof Jacques Grosset from the Johns Hopkins University School of Medicine in Baltimore, and his colleagues from the HZI and Sanofi scientists, initially focused on the natural substance called griselimycin. The potential of this natural substance, was discovered in the 1960s. However, due to the success of other tuberculosis medications and its low efficacy in an infection model, the substance was not developed any further at the time.

"We resumed the work on this agent and optimised it such that it shows excellent activity in the infection model - even against multi-resistant tuberculosis pathogens," says Müller. In the course of their work, the scientists discovered that cyclohexylgriselimycin, a variant of griselimycin, is particularly effective against Mycobacterium tuberculosis, both in cells and in the animal model. Importantly, cyclohexylgriselimycin was effective when administered orally, which is key in tuberculosis treatment, non-orally available drugs are extremely burdensome to administer daily during the many months of treatment. Moreover, combining this substance with current TB antibiotics increases the efficacy compared to the antibiotic cocktail that is usually administered.

Scientists identify new agent to combat tuberculosis

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

In continuation of my update on Bedaquiline

While an effective treatment is available for combating multidrug-resistant tuberculosis, it carries serious side effects for patients. New research conducted at the Center for Tuberculosis Research at the Johns Hopkins University School of Medicine shows that lower doses of the toxic drug bedaquiline — given together with verapamil, a medication that's used to treat various heart conditions — can lead to the same antibacterial effects as higher toxic doses of bedaquiline. The combination of the two drugs could potentially shorten treatment time, reduce the side effects of bedaquiline and improve patient outcomes for those suffering from TB.

The study will be published in the January 2014 issue of Antimicrobial Agents and Chemotherapy. The lead author is William Bishai, M.D., Ph.D., co-director of the Center for Tuberculosis Research.

"Using a mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses," says Shashank Gupta, Ph.D., a research fellow at Johns Hopkins. "A lower dose of bedaquiline will cause no or less severe side effects."

Two years ago, bedaquiline became the first drug in the last four decades to be approved by the U.S. Food and Drug Administration for the treatment of multidrug-resistant TB. The drug works by inhibiting an enzyme used by Mycobacterium tuberculosis to replicate and spread throughout the body. While it can be a lifesaving therapy against one of the world's deadliest diseases, bedaquiline can also cause serious side effects in the heart and liver. Therefore, strategies to reduce the dose of bedaquiline while retaining its antibacterial activity would provide significant benefits to patients.

"Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve multidrug-resistant TB treatment outcomes," says Gupta.

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

Diabetes drug can boost efficacy of TB medication without causing drug resistance

In continuation of my update on Metformin

A more effective treatment for tuberculosis (TB) could soon be available as scientists have discovered that Metformin (MET), a drug for treating diabetes, can also be used to boost the efficacy of TB medication without inducing drug resistance.

This discovery was made by a team of international scientists led by the Singapore Immunology Network (SIgN), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore.

TB is an air-borne infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb), which often infects the lungs. Even though drugs are available to treat the disease, TB continues to be a major threat to public health, killing close to 1.5 million people every year .

Conventional drugs used to treat TB usually adopt a pathogen-targeted strategy which attacks and kills bacteria directly. This approach has caused Mtb strains to acquire drug resistance, making existing treatments become increasingly ineffective and resulting in a pressing need to design new therapeutic strategies for the disease.

MET as an adjunct treatment for TB

The team of scientists led by SIgN began searching for drugs that could control Mtb replication indirectly. They screened FDA-approved drugs and identified MET, an old anti-diabetic drug that could defend Mtb invasion without targeting the bacteria directly. Instead, MET targets the host cells to trigger the production of a chemical which then damages Mtb and stops its replication. Such indirect, host-targeted approach is less likely to engender drug resistance. The team also discovered that MET improves the efficacy of conventional anti-TB drugs when used in combination with them.

The scientists then validated the findings with patient data provided by the Tuberculosis Clinical Unit at the Tan Tock Seng Hospital, and consequently verified that the use of MET is indeed associated with improved TB control and decreased disease severity. This anti-diabetic drug is therefore a promising adjunctive therapy that could enhance the effectiveness of existing TB treatments. As it is a drug that is currently in use, another benefit of using MET as an adjunct treatment for TB is that it is likely to shorten the time required for clinical trials.

Diabetes drug can boost efficacy of TB medication without causing drug resistance

Researchers uncover how malaria parasite becomes resistant to fosmidomycin drug

Researchers have uncovered a way the malaria parasite becomes resistant to an investigational drug. The discovery, at Washington University School of Medicine in St. Louis, also is relevant for other infectious diseases including bacterial infections and tuberculosis.

The study appears July 24 in Nature Communications.

Many organisms, including the parasite that causes malaria, make a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy, whether plants, animals or bacteria. In malaria, the investigational drug fosmidomycin blocks isoprenoid synthesis, killing the parasite. But over time the drug often becomes less effective.

"In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study," said senior author Audrey R. Odom, MD, PhD, assistant professor of pediatrics. "We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?"

Fosmidomycin, an antibiotic, is being evaluated against malaria in phase 3 clinical trials in combination with other antimalarial drugs.

Using next-generation sequencing technology, the research team compared the genetics of malaria parasites that responded to the drug to the genetics of malaria parasites that were resistant to it. With this approach, Odom and her colleagues found mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.

"The PfHAD1 protein is completely unstudied," Odom said. "It's a member of a larger family of proteins, and there are almost no biological functions assigned to them."

In malaria parasites, Odom's team showed that the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing. Since isoprenoids are necessary for life, it's not clear why the organism would purposefully slow down isoprenoid production.

Ref : http://www.nature.com/ncomms/2014/140724/ncomms5467/full/ncomms5467.html

Researchers uncover how malaria parasite becomes resistant to fosmidomycin drug

Multitarget TB drug could treat other diseases, evade resistance -- ScienceDaily

A drug under clinical trials to treat tuberculosis could be the basis for a class  of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study. The team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug can be tweaked to target other pathogens from yeast to malaria  and how targeting multiple pathways reduces the probability of pathogens becoming resistant.

Led by U. of I. chemistry professor Eric Oldfield, the team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug  can be tweaked to target other pathogens from yeast to malaria -- and how targeting multiple pathways reduces the probability of pathogens becoming resistant. SQ109 is made by Sequella Inc., a pharmaceutical company. 

"Drug resistance is a major public health threat," Oldfield said. "We have to make new antibiotics, and we have to find ways to get around the resistance problem. And one way to do that is with multitarget drugs. Resistance in many cases arises because there's a specific mutation in the target protein so the drug will no longer bind. Thus, one possible route to attacking the drug resistance problem will be to devise drugs that don't have just one target, but
two or three targets."

Oldfield read published reports about SQ109 and realized that the drug would likely be multifunctional because it had chemical features similar to those found in other systems he had investigated. The original developers had identified one key action against tuberculosis -- blocking a protein involved in building the cell wall of the bacterium -- but conceded that the drug could have other actions within the cell as well since it was found to kill other bacteria and
fungi that lacked the target protein. Oldfield believed he could identify those actions  and perhaps improve upon SQ109. 

"I was reading Science magazine one day and saw this molecule, SQ109, and I thought, that looks a bit like molecules we've been studying that have multiple targets," Oldfield said. "Given its chemical structure, we thought that some of the enzymes that we study as cancer and antiparasitic drug targets also could be SQ109 targets. We hoped that we could make some analogs that would be more potent against tuberculosis, and maybe even against parasites.

More : http://pubs.acs.org/doi/abs/10.1021/jm500131s

Multitarget TB drug could treat other diseases, evade resistance

Researchers identify potential way to combat TB

Researchers have identified a potential way to manipulate the immune system to improve its ability to fight off tuberculosis (TB).

TB is a major problem for both humans and cattle and the new findings could help scientists to create better drugs to combat the disease in both.

The disease is caused by the bacterium Mycobacterium tuberculosis, which infects the lungs. The mycobacteria are able to establish persistent TB infections by taking up residence in macrophages - cells of the immune system that would normally destroy invading microorganisms.

Now, in early stage research published in the Journal of Biological Chemistry, researchers from Imperial College London and Stanford University have revealed precisely how unusual sugars on the surface of the mycobacteria that cause TB are able to latch onto the macrophages and disarm them. They now hope that scientists at Imperial and elsewhere can use this knowledge to develop small molecule drugs that latch tightly onto the same site.

These drugs could potentially fight tuberculosis in a number of ways, say the researchers. They could create a barrier to prevent the mycobacteria from attaching to the macrophages; they could transport drugs to kill the mycobacteria; or they could change how the macrophages behave, so that they destroy the mycobacteria rather than harbouring them.

Professor Kurt Drickamer, a lead author of the research from the Department of Life Sciences at Imperial College London, said: "TB is hard to fight effectively because it can hide inside the cells of the immune system that should be able to destroy it. We were surprised to find that there is an extensive interaction between the macrophage and one particular type of molecule on the surface of the mycobacteria. The nature of the interaction gives us hope that we can make simple molecules that block the ability of the mycobacteria to subvert the macrophages.

Ref : http://www.jbc.org/content/288/40/28457.abstract?sid=eeb4801e-b429-4bbf-b0cd-446229088668

"Researchers identify potential way to combat TB

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction : Nature Communications : Nature Publishing Group

In a striking, unexpected discovery, researchers at Albert Einstein College of Medicine of Yeshiva University have determined that vitamin C kills drug-resistant tuberculosis (TB) bacteria in laboratory culture. The finding suggests that vitamin C added to existing TB drugs could shorten TB therapy, and it highlights a new area for drug design.

Dr. Jacobs and his colleagues observed that isoniazid-resistant TB bacteria were deficient in a molecule called mycothiol. "We hypothesized that TB bacteria that can't make mycothiol might contain more cysteine, an amino acid," said Dr. Jacobs. 

"So, we predicted that if we added isoniazid and cysteine to isoniazid-sensitive M. tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture  something totally unexpected."

The Einstein team suspected that cysteine was helping to kill TB bacteria by acting as a "reducing agent" that triggers the production of reactive oxygen species (sometimes called free radicals), which can damage DNA.

"To test this hypothesis, we repeated the experiment using isoniazid and a different reducing agent vitamin C," said Dr. Jacobs. "The combination of isoniazid and vitamin C sterilized the M. tuberculosis culture. We were then amazed to discover that vitamin C by itself not only sterilized the drug-susceptible TB, but also sterilized MDR-TB and XDR-TB strains."

To justify testing vitamin C in a clinical trial, Dr. Jacobs needed to find the molecular mechanism by which vitamin C exerted its lethal effect. More research produced the answer: Vitamin C induced what is known as a Fenton reaction, causing iron to react with other molecules to create reactive oxygen species that kill the TB bacteria.

"We don't know whether vitamin C will work in humans, but we now have a rational basis for doing a clinical trial," said Dr. Jacobs. "It also helps that we know vitamin C is inexpensive, widely available and very safe to use. At the very least, this work shows us a new mechanism that we can exploit to attack TB.".....

Ref : http://www.einstein.yu.edu/news/releases/907/study-finds-vitamin-c-can-kill-drug-resistant-tb/


Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction : Nature Communications : Nature Publishing Group

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

In continuation of my update on bedaquiline...

Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.

The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.

Sirturo’s manufacturer, Janssen Therapeutics, will distribute the drug from a single source and will provide educational materials to help ensure the drug is used appropriately.

Sirturo’s safety and effectiveness were established in 440 patients in two Phase 2 clinical trials. Patients in the first trial were randomly assigned to be treated with Sirturo plus other drugs used to treat TB, or a placebo plus other drugs used to treat TB. All patients in the second trial, which is ongoing, received Sirturo plus other TB drugs. Both studies were designed to measure the length of time it took for a patient’s sputum to be free of M. tuberculosis (sputum culture conversion, or SCC).

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

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

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

In continuation of my update on Sirturo

On Dec. 28, the U.S. Food and Drug Administration approved Sirturo (bedaquiline) as part of combination therapy to treat adults with multi-drug resistant pulmonary tuberculosis (TB) when other alternatives are not available.

Bedaquiline (also known as Sirturo, TMC207 or R207910 see structure) is an diarylquinoline anti-tuberculosis drug, which was discovered by Koen Andries and his team at Janssen Pharmaceutica. It was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting Late-Breaker Session, after the drug had been in development for over 7 years, and a trial of 47 patients showed that it is effective in the treatment of M. tuberculosis.

Multi-drug resistant TB occurs when M. tuberculosis becomes resistant to isonazid and rifampin, two powerful drugs most commonly used to treat TB. Sirturo is the first drug approved to treat multi-drug resistant TB and should be used in combination with other drugs used to treat TB. Sirturo works by inhibiting an enzyme needed by M. tuberculosis to replicate and spread throughout the body.

“Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who have don’t have other therapeutic options available,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options.”

Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.

The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

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

Beating Drug-Resistant TB.....

An antibiotic produced naturally by common soil bacteria kills Mycobacterium species that cause various human diseases, including tuberculosis (TB), according to a report published Monday (September 17) in EMBO Molecular Medicine. The antibiotic even kills drug-resistant strains that escape current TB treatments.

“I seldom get so tickled when I read a paper,” said William Jacobs, a microbiologist and immunologist at the Albert Einstein College of Medicine in New York, who did not participate in the research. The emergence of multidrug resistant strains of Mycobacterium tuberculosis “is a big problem,” he said. “This could be a godsend.”

Tuberculosis infections are commonly treated with a mixture of antibiotics, including one called isoniazid, which Jacobs described as “the cornerstone of TB therapy.”  Unfortunately, the most common drug-resistant strains of M. tuberculosis are isoniazid-resistant, he said.

Many researchers, including Stewart Cole, chair of the microbial pathogenesis department at the École Polytechnique Fédérale de Lausanne in Switzerland, have thus been searching for new M. tuberculosis-killing drugs. “In the past we’ve been working a lot on TB drug discovery using target-based approaches… [but] this has been spectacularly unsuccessful,” said Cole. So instead, he and his colleagues looked back over decades of academic literature searching for reports of natural compounds with M. tuberculosis-killing activity.

They found pyridomycin (see above structure). First described in the 1950s, the drug was reportedly produced by the bacteria Streptomyces pyridomyceticus and Dactylosporangium fulvum. Surprisingly, little was known about pyridomycin—perhaps, Cole suggested, because isoniazid was discovered around the same time and simply stole the limelight.

Cole’s team grew cultures of D. fulvum bacteria, figured out how to isolate and purify pyridomycin, and then showed that the drug was indeed capable of killing M. tuberculosis, as well as many otherMycobacterium species, in culture.

This indiscriminate Mycobacterium-killing ability is a bonus, said Cole. “One of the problems with isoniazid is that it only works against TB,” he said. “If pyridomycin makes it into the clinic, it could have applications in leprosy or Buruli ulcer or atypical mycobacterial infections that can occur in cystic fibrosis patients.”

The team went on to identify the bactericidal target of pyridomycin—a protein called inhA, which is involved in synthesis of bacterial cell wall components. As it happens, inhA is the same protein targeted by isoniazid, but there is a difference in the two drugs’ mechanisms. While isoniazid is a pro-drug that requires activation by an intracellular enzyme called KatG before it can bind to inhA, pyridomycin binds inhA directly.

This is an important distinction, explained Valerie Mizrahi, director of the Institute of Infectious Disease and Molecular Medicine at Cape Town University, South Africa, who was not involved in the study. The overwhelming majority of drug resistance mutations in M. tuberculosis occur in the KatGgene, she explained, and such mutant strains should not be resistant to pyridomycin. Indeed, the team showed that clinical isolates of isoniazid-resistant M. tuberculosis carrying KatG mutations were killed effectively by pyridomycin. “The efficacy against drug resistant forms of M. tuberculosis is particularly encouraging,” Mizrahi said.

There is, however, much to be done before pyridomycin can be used in the clinic. “We would [need to] test that it works in animal models and that it is safe and doesn’t have any side effects,” said Cole. “That will take a couple of years.”

“It’s a long journey,” agreed Mizrahi, “but the big plus is that they don’t really need to validate inhA as a drug target because inhA is already the most well validated drug target out there… [so] it has got a good head start.”

Ref : http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201689/abstract

New Drug, Bedaquiline to Tackle Resistant TB

Johnson & Johnson said that it is seeking U.S. approval for the first new type of medicine to fight deadly tuberculosis in more than four decades.

The experimental drug, called bedaquiline (discovered by Koen Andries, see structure), also would be the first medicine specifically for treating multi-drug-resistant tuberculosis. That's an increasingly common form in which at least two of the four primary TB drugs don't work.

Mode of action : Bedaquiline affects the proton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase

Tuberculosis, caused by bacterial infection of the lungs and other body areas, is the world's No. 2 killer of adults among infectious diseases.

J&J's Janssen Research & Development unit created the drug, which was tested in several hundred patients with multidrug-resistant tuberculosis in two mid-stage studies lasting for six months. Some patients were studied for about 1 1/2 years.

The company this fall is to begin late-stage testing that will compare bedaquiline to dummy pills over nine months in about 600 patients; each will also take six other drugs that are the standard treatments for tuberculosis. That study is aimed at seeing whether treatment for resistant tuberculosis can be reduced to nine months from the current 18 to 24 months recommended by the World Health Organization.

Roughly one-third of the world's population is estimated to be infected with the bacteria causing tuberculosis. It remains latent in most people for many years but can be activated by another infection or serious health problem.

TB is rare in the U.S. but kills about 1.4 million people a year worldwide, with about 150,000 of those succumbing to the increasingly common multidrug-resistant forms.

Janssen's head of infectious diseases, Dr. Wim Pays, said the company will also apply for approval of bedaquiline in other countries where TB is very common.

The disease is a serious problem in developing countries because it takes so long to cure and many patients stop taking their pills once they begin to feel better. That helps bacteria still alive in the patient to develop resistance to the medicines already taken, making future treatment much more difficult.

Ref : http://www.inpharm.com/news/173302/janssen-submits-tuberculosis-pill-fda

Experimental drug tested against multi-drug resistant TB

"Researchers who tested a novel type of antibiotic against multi-drug-resistant tuberculosis [MDR-TB] are reporting that nearly half of patients who got the new drug cleared the bacteria from their lung fluid in two months," according to a study published  in the New England Journal of Medicine. Japanese pharmaceutical company Otsuka developed the experimental drug, delamanid (see structure), and "also designed and financed the clinical trial, which took place in 17 medical centers across nine countries." 

 "'We've invested a lot of time and money to develop this drug, but we are not seeking robust sales growth immediately,' Masuhiro Yoshitake, Otsuka's head of tuberculosis projects, said in an interview," Bloomberg Businessweek reports. "We want to begin selling to people who know how to use the drug," he added, the news service notes. "Doctors must balance the need to fight hard-to-treat cases against prolonging the medicine's potency,"

More : http://www.nejm.org/doi/full/10.1056/NEJMoa1112433

Experimental drug tested against multi-drug resistant TB

Novel two-drug combination cures young patient with extensively drug-resistant tuberculosis

The combination of meropenem (above structure)  with clavulanate (right structure-potassium salt)  has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. Researchers report the successful use of this combination in association with linezolid (below structure)  in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.

Ref : 1.Meropenem/Clavulanate and Linezolid Treatment for Extensively Drug-Resistant Tuberculosis

    2. http://www.einstein.yu.edu/uploadedFiles/PHD/2010%20Faculty%20Research%20Book.pdf

World's first urine-based tuberculosis diagnostics tool

World's first urine-based tuberculosis diagnostics tool

New substance (Benzothiazin derivative) to tackle drug resistant tuberculosis...

Project NM4TB which gathers 18 research teams from 13 countries, discovered a novel class of substances, called benzothiazinones (BTZ-see structure), that could be used in the treatment of tuberculosis and drug resistant tuberculosis.

Prof Stewart Cole, Dr Vadim Makarov, Dr Ute Möllmann, Prof Giovanna Riccardi, and their colleagues have identified a novel class of compounds called benzothiazinones (BTZ) that act by preventing the TB bacterium from constructing its cell wall. In particular, one member of the class, BTZ043 was extremely potent, killing the TB agent, both in test tube experiments and in mouse models of the disease. BTZ043 is as effective as the two main drugs (Isoniazid and Rifampicin) in reducing the bacterial levels in the lungs and spleens of infected mice. The target of the new class of compounds is a component of Mycobacterium’s cell-wall-building machinery that has never before been used as a drug target. The most advanced compound of this new class, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB. 

These substances act by preventing the bacteria that cause tuberculosis from constructing their cell wall. This discovery represents an important breakthrough in the battle against tuberculosis as the most advanced compound of this new class, BTZ043, is also effective against extensively drug resistant tuberculosis (XDR-TB).

More... : 

Immunitor reports positive safety imm01 clinical trial against tuberculosis

Immunitor reports positive safety imm01 clinical trial against tuberculosis