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

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

FDA Approves Pretomanid for Highly Drug-Resistant Forms of Tuberculosis

In continuation of my update on Pretomanid

 Pretomanid, a novel compound developed by the non-profit organization TB Alliance, was approved by the U.S. Food & Drug Administration (FDA) today for treating some of the most drug-resistant forms of tuberculosis (TB).1 The new drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) as part of a three-drug, six-month, all-oral regimen for the treatment of people with extensively drug-resistant TB (XDR-TB) or multidrug-resistant TB (MDR-TB) who are treatment-intolerant or non-responsive (collectively “highly drug-resistant TB”).1,2

The LPAD pathway was established by FDA as a tool to encourage further development of antibacterial and antifungal drugs to treat serious, life-threatening infections that affect a limited population of patients with unmet needs. 

“FDA approval of this treatment represents a victory for the people suffering from these highly drug-resistant forms of the world’s deadliest infectious disease,” said Mel Spigelman, MD, president and CEO of TB Alliance. “The associated novel regimen will hopefully provide a shorter, more easily manageable and highly efficacious treatment for those in need.”

The three-drug regimen consisting of bedaquiline, pretomanid and linezolid – collectively referred to as the BPaL regimen – was studied in the pivotal Nix-TB trial across three sites in South Africa. The trial enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB.2

Nix-TB data have demonstrated a successful outcome in 95 of the first 107 patients after six months of treatment with BPaL and six months of post-treatment follow-up.2 For two patients, treatment was extended to nine months. The new drug application contains data on 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy.2 Pretomanid has been clinically studied in 14 countries.

TB, in all forms, must be treated with a combination of drugs; the most drug-sensitive forms of TB require six months of treatment using four anti-TB drugs.3 Treatment of XDR-TB or treatment-intolerant/non-responsive MDR-TB has historically been lengthy and complex; most XDR-TB patients currently take a combination of as many as eight antibiotics, some involving daily injections, for 18 months or longer.3,4 Prior to recent introduction of new drugs for drug-resistant TB, the World Health Organization (WHO) has reported estimates for treatment success rates of XDR-TB therapy at approximately 34 percent and about 55 percent for MDR-TB therapy.4

“Until very recently, people infected with highly drug-resistant TB had poor treatment options and a poor prognosis,” said Dr. Francesca Conradie, principal investigator of the Nix-TB trial. “This new regimen provides hope with 9 out of 10 patients achieving culture negative status at 6 months post-treatment  with this short, all-oral regimen."

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. TB Alliance acquired the developmental rights to the compound in 2002. It has been developed as an oral tablet formulation for the treatment of TB in combination with bedaquiline and linezolid, two other anti-TB agents, and is now indicated for use in a limited and specific population of patients.1 Adverse reactions reported during the Nix-TB trial of the BPaL regimen include hepatotoxicity, myelosuppression, as well as peripheral and optic neuropathy.1 Please see additional safety information in the Important Safety Information below.

Pretomanid is only the third new anti-TB drug approved for use by FDA in more than 40 years, as well as the first to be developed and registered by a not-for-profit organization.5,6 Pretomanid was granted Priority Review, Qualified Infectious Disease Product, and Orphan Drug status. As a product development partnership, TB Alliance has collaborated with and received significant support from numerous governments, academia, philanthropic institutions, the private sector, civil society organizations and other partners over the course of pretomanid’s development.

Pretomanid is expected to be available in the United States by the end of this year. In addition to the U.S. FDA, TB Alliance has submitted pretomanid as part of the BPaL regimen for review by the European Medicines Agency and has provided data to the World Health Organization for consideration of inclusion in treatment guidelines for highly drug-resistant TB.

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

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... : 

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

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

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

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.

TB disease mechanism and the molecule to block It - discovered ......

We know about the drug resistant tuberculosis and the havoc its causing, so there is an urgent need to  develop new drugs that can be useful. (have covered some articles on  drug development  for drug resistant TB in my earlier blogs). Many groups have tried to explain the resistance,  but now  researchers from Indiana University School of Medicine have identified a mechanism used by the tuberculosis bacterium to evade the body's immune system and have identified a compound that blocks the bacterium's ability to survive in the host, which could lead to new drugs to treat tuberculosis. 

The focus of the research was TB actions inside macrophages (infection fighting cells in the body's immune system). Macrophage cells' tools include the production of special proteins called cytokines to attack foreign invaders. Infected macrophages can also initiate a self-destruction mechanism called apoptosis, which signals other immune system cells to mount a defense against the infection. 

TB bacteria are able to disable the macrophage defenses by secreting virulent factors into the host. The IU team found that the actions of a particular virulent factor a protein phosphatase enzyme called mPTPB  blocked both the production of the infection-fighting cytokines, and the macrophage's self-destruct system. 

As for as my knowledge goes,  phosphatases  (VE-PTP, Cdc25A, PTP1b, VHR, Shp-2, MptpA und MptpB) the  key regulators of various life processes are being studied for the diverse activities. The following is the brief summary ;

a). VE-TPT inhibition is very promising in the development of antiangiogenesis inhibitors in cancer therapy.
b). Cdc25A influences cell cycle regulation and may also be a target of interest in cancer therapy.
c). The phosphatase MptpB, from Mycobacterium tuberculosis, influences the host's immune 
     reaction in a tuberculosis infection.
d) VHR dephosphorylates MAP kinases in the activation loop THX, which plays an important role in signal
    transduction processes.
e) Inhibiting MptpB and Shp-2 opens up new directions in the search for antibiotics and
f) The Ptp1B enzyme plays an important role in developing a medicine against type 2 diabetes and the
   metabolic syndrome.

Though many researchers  tried to study the mechanism of action by which the  tuberculosis bacterium is getting resistance,  this group has come up with a drug and this is of great significance in my opinion.

Using combinatorial chemical synthesis and high-throughput screening, (HTS) the researchers developed the I-A09 compound, which successfully blocked the action of mPTPB. Tests involving live TB bacteria were conducted at the Institute of Tuberculosis Research, University of Illinois at Chicago. 

As per the claim by the lead researcher, Dr. Zhong-Yin Zhang, compound I-A09 is being evaluated in a TB animal model at the Johns Hopkins University School of Public Health. More potent forms of the I-A09 compound are being pursued by the IU team for possible future clinical testing. Hope the team  will come up with a solution to this problem in the days to come...

Ref : http://www.medicine.indiana.edu/news_releases/viewRelease.php4?art=1232

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

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

New insight for design of novel antibiotic derivatives for drug resistant microorganisms...

Viomycin and Capreomycin (a group of nonribosomal peptide antibiotics) belong to the tuberactinomycin (an essential component in the drug cocktail currently used to fight infections of Mycobacterium tuberculosis) Are among the most effective antibiotics against multidrug-resistant tuberculosis. Viomycin was the first member of the tuberactinomycins to be isolated and identified and was used to treat TB until it was replaced by the less toxic, but structurally related compound, Capreomycin. The tuberactinomycins target bacterial ribosomes, binding RNA and disrupting bacterial protein biosynthesis.

Now Dr. Steitz and his colleagues at Yale's Department of Molecular Biophysics and Biochemistry, have identified two structures of tuberactinomycins bound to the ribosome. The researchers claims that,   the identification of these structures provides an insight for the design of novel antibiotic derivatives that could be effective against a variety of drug resistant microorganisms.

As per the claim by Dr.Steitz, both antibiotics (Viomycin and Capreomycin) bind to the same site on the ribosome, which lies at the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit. The structures of these complexes suggest that the tuberactinomycins inhibit translocation by stabilizing the tRNA in the A site in the pretranslocation state. In addition, these structures show that the tuberactinomycins bind adjacent to the binding sites for the paromomycin and hygromycin B antibiotics, which may enable the development of new derivatives of tuberactinomycins that are effective against drug-resistant strains. The authors have presented two crystal structures of the 70S ribosome in complex with three tRNAs and bound to either viomycin or capreomycin at 3.3-and 3.5-Å resolution, respectively in "Nature Structural & Molecular Biology 14 February 2010 ".

Interestingly, Dr. Steitz was awarded the 2009 Nobel Prize in Chemistry   for his groundbreaking work determining a high resolution crystal structure of the 50S subunit of the ribosome which has proved to be a major target for antibiotic development.

Hope this discovery will lead to a new insight for design of novel antibiotic derivatives that could be effective against a variety of drug-resistant microorganisms ....

Ref: http://www.rib-x.com/news_and_events/release_2010_02_16

Eliminating inherent drug resistance in tuberculosis....

In continuation of my update on drug resistant TB and the drug development for TB, I found this info interesting to share with.

Dr. John Blanchard of the Albert Einstein College of Medicine has come up with really  interesting  findings about how to "eliminate inherent drug resistance in tuberculosis".   

When the M. tuberculosis genome was sequenced a few years ago, the presence of  beta-lactamase enzyme was discovered. Most scientists didn't pay much attention to this discovery and beta-lactams   never have been systematically used to treat TB. However Dr. John,  thought it would be an attractive therapeutic target, considering several beta-lactamase inhibitors had been developed for other bacteria.

If we could inactivate this inactivator enzyme, it would expose TB bacteria to a whole new range of antibiotics," he says. 

While M. tuberculosis was resistant to most beta-lactamase inhibitors,  Blanchard's group found that the drug clavulanate was effective in shutting down the TB enzyme. 

The combination of clavulanate (see above right structure- its potassium salt) with the beta-lactam   meropenem (see below: left structure) could effectively sterilize laboratory cultures of TB within two weeks, including several XDR-strains (XDR strains are even more resilient than multi-drug resistant (MDR) strains).  Blanchard notes this finding was exciting since, despite such high rates of drug resistance, research into new TB drugs is not a high priority in industrialized countries (for socio-economic reasons), and thus the best short-term approach might be identifying other already FDA approved antibiotics that are effective against TB -like meropenem and clavulanate.

Blanchard is currently progressing with the next steps of the therapeutic process, which includes both detailed animal studies and setting up some small-scale trials with XDR-TB patients in developing nations...

(Source : a presentation at the American Society for Biochemistry and Molecular Biology’s annual meeting, titled “Drug resistance in tuberculosis,” by Dr. John Blanchard).

Ref : http://www.asbmb.org/News.aspx?id=7470&terms=John+Blanchard

PA-824 - Aerosol: New Tool Against Tuberculosis?

We know the epidemic rates of HIV/TB coinfection as well as emerging multidrug-resistant  (MDR) and extensively drug-resistant (XDR) TB strains those are contributing to increased TB-associated deaths worldwide. 

Now PA-824 (see structure), a compound capable of being formulated into a dry powder, has not only shown promising activity against MDR (multidrug-resistant tuberculosis) and XDR (extensively drug-resistant tuberculosis, or latent TB) but has also proven safe and effective in patients coinfected with HIV and TB. Previous studies showed that PA-824 was well-tolerated in tablet form, however, side effects such as headache and stomach discomfort were reported. Aerosol delivery of PA-824 directly to the primary site of infection would limit systemic exposure and ultimately eliminate potentially bothersome side effects.

About  PA-824 :

Nitroimidazoles are widely used drugs in humans for a variety of primarily anaerobic microbial infections. Metronidazole, a 5-nitroimidazole, is an important bactericidal agent for the treatment of anaerobic infections  and shows excellent selective toxicity toward anaerobic bacterial and protozoal pathogens. This class of compounds has only recently begun to be explored for Mtb, because only anaerobic activity of metronidazole against Mtb has been reported. Bicyclic 4-nitroimidazoles such as PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) have inhibitory activity against aerobically growing and nonreplicating anaerobic Mtb. Although anaerobic conditions have not been demonstrated during TB disease in humans, various authors have suggested that an anaerobic microenvironment may contribute to a nonreplicating state that may be linked with latent disease in humans. Thus, PA-824 has been developed, in part, because it may be a promising lead for therapy against latent disease that may be linked to anaerobically persisting bacilli. The Global Alliance for TB Drug Development has recently initiated phase-I clinical trials with PA-824 

Researchers from the University of North Carolina School of Pharmacy, Chapel Hill, North Carolina; and Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, lead by  Dr. Anthony J Hickey  have achieved this interesting finding, i.e., potential use of PA-824 dry powder aerosols in the treatment of TB.

In the study guinea pigs were used to evaluate the effects of PA-824 aerosols on TB infection. One month following infection with TB some guinea pigs received high daily aerosol treatments while others received low daily treatments for 4 weeks. Lung and spleen analysis of guinea pigs receiving the high dose of aerosol PA-284 showed less inflammation, bacterial burden and tissue damage.

"The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB,” say the researchers".

Ref : http://aac.asm.org/cgi/content/abstract/54/4/1436.

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

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

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

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

A New approach for the TB drug discovery ?

We are aware that the development of new drugs to combat tuberculosis (TB) has become urgent, as strains of TB resistant to all major anti-TB drugs have emerged worldwide. The World Health Organization estimates that one third of the world's population is asymptomatically infected with TB and that ten percent will eventually develop the disease. More over people with HIV are more prone to TB and hence the need is urgent. As it has happened in other fields of drug discoveries, its something really interesting now it’s the turn of TB drugs, thanx to Barbara Gerratana, Asst., Prof.,. of Chemistry and Biochemistry, university's College of Chemical and Life Sciences, Maryland for their achievement. The significance of the research lies in the fact that “ the NAD+ synthetase enzyme is essential for the survival of the tuberculosis bacteria and hence it can be considered as a drug target.”. So even the structure based inhibitors specific for M. tuberculosis NAD+ synthetase, can be tried and tested for the tuberculosis activity.

Even the experts are really happy over the outcome of the research and following are the lines of appreciation from Clifton E. Barry, Chief of the Tuberculosis Research Section of the Intramural Research Division of the National Institute of Allergy and Infectious Diseases “NadE [NAD+ synthetase] represents one of a small handful of TB drug targets that has iron-clad validation, the lack of a crystal structure was the only serious impediment to drug development and this study represents a hugely important step forward. Inhibiting NadE even kills non-replicating cells, so this discovery may well benefit the one-third of the human population that carries latent bacteria.".

Most interesting part of the research is the fact that “there are only two pathways involved in producing NAD+ in the tuberculosis bacterium and both depend on the activity of NAD+ synthetase to obtain NAD+ (unlike in human beings, where in several different complex pathways..). One can target these two pathways and get good drugs, those are essential and there by one can overcome the drawbacks of the present drugs (current treatment of tuberculosis targets the active tuberculosis bacterium and has little effect on the non-replicating bacterium). Once again congrats for the research group……

Improved efficacy of tuberculosis vaccine ?

We know that BCG (Bacille Calmette-Guérin) is a live but weakened form of a bacterium, M. bovis, which causes tuberculosis in cattle. It is sufficiently related to the human pathogen to stimulate production of specialized immune cells that fight off TB infection when it is injected into a person as a vaccine. The bacilli have retained enough strong antigenicity to become a somewhat effective vaccine for the prevention of human tuberculosis. At best, the BCG vaccine is 80% effective in preventing tuberculosis for a duration of 15 years, however, its protective effect appears to vary according to geography.

Many attempts have been made to improve the vaccine by incorporating antigens (molecular components of the bacteria) to induce a stronger immune response. However, tuberculosis and BCG have evasive mechanisms that prevent the development of stronger immune responses. We read oftenly in news paper, about the drug resistant strains and use of combined drugs. Now thanx to the two research groups from UT Health Science Center at Houston. The importance of this research is in the fact that the two groups investigated mechanisms by which BCG evades immune stimulating mechanisms and devised two means to neutralize them.

1. scientists used genetically-modified organisms and
2. a drug used for organ transplantation (Rapamycin, see the structure)to block BCG's evasive mechanisms, causing it to induce stronger immune responses.

This dual approach to the BCG vaccine was associated with a tenfold increase in the number of TB organisms killed and a threefold increase in the duration of protection in tests with an NIH-approved mouse model, Dr. Jagannath said.

The research is of great importance because of the fact that "it has countered the ability of TB organisms to subvert immunization", (Tuberculosis hides in cells so the antigens are not recognized by the immune system. The BCG vaccine also does the same thing). The role of the drug is of great importance, i.e., it modulates the movement of particles in cells, would cause BCG antigens to enter pathways leading to improved immunization. I would say one more significant contribution(or else one more serendipity !) of the drug apart from bieng used in 1. treatment of cancer and inflammation 2. in significantly reducing the frequency of acute kidney transplant rejection.

Though further research to substantiate the claim is essential. Its a good beginning in this direction for the improved efficay of the vaccine.. Congrats Dr. Jagannath and group.. More...