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

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

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

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

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

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

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

Body's own proteins may lead the way in global fight against tuberculosis

Body's own proteins may lead the way in global fight against tuberculosis

New research finding may change direction of vaccine research for M. tuberculosis

New research finding may change direction of vaccine research for M. tuberculosis

New details of tuberculosis protein-cleaving machinery revealed

New details of tuberculosis protein-cleaving machinery revealed

PEPCK (phosphoenolpyruvate carboxykinase) a potential target for drugs that fight tuberculosis.

 In continuation of my update on tuberculosis and drug discovery ..... A new  research conducted at Weill Cornell Medical College sheds light on a previously unrecognized aspect of fatty acid metabolism that could potentially lead to new targets for drug therapy. A team led by Dr. Sabine Ehrt, professor of microbiology and immunology at Weill Cornell Medical College, reported that Mtb relies primarily on gluconeogenic substrates for in vivo growth and persistence, and that phosphoenolpyruvate carboxykinase (PEPCK see picture) plays a pivotal role in the growth and survival of Mtb during infections in mice, making PEPCK a potential target for drugs that fight tuberculosis.

Dr. Ehrt and her colleagues found a way to silence the gene encoding PEPCK in Mtb during mouse infections to assess the importance of gluconeogenesis for Mtb's ability to maintain a chronic infection.

 "Silencing a gene when the pathogen is not or only slowly replicating, after an infection has established, is an important tool for studying diseases such as TB, which can be dormant for years only to become active again years later." says Dr.Ehrt...

 It is especially challenging as the infection can lay dormant in the body even though there are no symptoms. Researchers investigated the metabolic requirements of Mtb during acute and chronic infections and found that the gluconeogenic enzyme PEPCK is critical for both.

Interestingly, the  study used a novel mass spectrometry-based metabolic profiling tool, developed at Weill Cornell (in collaboration with Agilent Technologies) by Dr. Kyu Rhee to biochemically examine Mtb carbon metabolism. As per the claim by the researchers,  the tool has provided the first direct insights into the metabolic architecture of Mtb.

 Though the current treatments used  to treat Mtb are effective, the treatment times are too long and the regimens too complex, which  leads to treatment failures (due to poor adherence and multi drug resistance).   We need new, safer drugs that work faster to eliminate tuberculosis.  Dr. Ehrt hopes that her work will eventually lead to new drug therapies to treat tuberculosis.....

Ref : http://www.pnas.org/content/early/2010/04/26/1000715107

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.

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

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

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

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

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

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

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

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