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Tuberculosis: a re-emergent killer

Pavia, Italy, 2 December 2014


Source: © 2014 University of Pavia


Because of the spread of M. tuberculosis strains multi-resistant to the drugs currently used in therapy, there is the need to have a higher number of molecules in the stages of pre-clinical and clinical development. The purpose of this project is to search for new compounds with anti-tuberculosis activity and to study their mechanisms of action and resistance. In our laboratory, we have identified the cellular target of a class of new anti-TB drugs, the benzothiazinones (BTZ). The target of BTZ is DprE1, an enzyme involved in cell wall biosynthesis, present only in bacterial cells. This drug is now in the final stage of pre-clinical development and will enter the clinical trials the next autumn.

New compounds will be tested against M. tuberculosis and the most effective ones will be selected for further analysis. More precisely, the funds raised through this campaign will be used to identify the target of a new drug, just found out and very active against multidrug-resistant strains. Finding the target means to know the mechanism of action of the drug, that is where it hits the molecule in the cell. Once identified, we can also improve the molecule and make it even more efficient.

Tuberculosis is a disease strongly increasing also due to the globalization effect, the easiness of individuals to travel the world and migration, which involves the arrival of people from areas of high tuberculosis endemicity. In addition, a recent study by the World Health Organization launched an alarming warning on antibiotic resistance: "Minor infections are likely to return to kill." Among the infections most at risk WHO includes tuberculosis.

REFERENCES

Tuberculosis: a re-emergent killer

The achieved results regarding benzothiazinones have been published in SCIENCE and the article has been cited as one of the "key papers" published in 2009 (see: Nature Medicines 15:1349)

Stop TB italia

Advisory board component of : innovative medicines for tuberculosis




Warm congratulations to Stewart Cole

Lausanne, Switzerland, 16 November 2014

Medal
Source: © 2014 EPFL


Professor Stewart Cole has been awarded the prestigious Emil von Behring Prize for his contributions to the field of tuberculosis.

Professor Stewart Cole, currently director of EPFL's Global Health Institute and Head of the Lab of Microbial Pathogenesis, has been awarded the 2014 Emil von Behring Prize from the University of Marburg. He is being recognized "for his outstanding work in the field of tuberculosis research", which includes groundbreaking publications on the genomics of Mycobacterium tuberculosis and Mycobacterium leprae. His current work focuses on the development and clinical testing of novel antibiotics against M. tuberculosis, which currently accounts for 1.5 million deaths each year (source: WHO).

The Emil von Behring Prize commemorates the homonymous scientist who won the first Nobel Prize in Physiology or Medicine in 1901. Emil Adolf von Behring (1854 - 1917) achieved fame for developing a serum therapy against diphtheria and tetanus, two diseases that claimed numerous lives of children and soldiers at the time.

Medal2

The Emil von Behring Prize is awarded every two years by the (Philipps-) University of Marburg to honor special scientific achievements in medical, veterinary and scientific areas, with an emphasis on immunology and disease control. The Prize is one of the most prestigious German awards, and consists of a medal with von Behring's engraving and a sum of €20,000, donated by the Marburg-based Novartis Vaccines and Diagnostics.

The Global Health Institute is one of the four research Institutes homed at the EPFL School/Department of Life Sciences.

http://actu.epfl.ch/news/warm-congratulations-to-stewart-cole-2/






Innovative Medicines for Tuberculosis present at the highly successful Planèt Santé Exhibition

Lausanne, Switzerland, 13-16 November 2014

Planet sante
Source: © 2014 iM4TB


The first Planèt Santé (Healthy Planet) exhibition, which took place between 13 and 16 November 2014, closed with a record number of 28,000 entries, which was three times more than expected. The exhibition was even a victim of its own success as the capacity of the welcome desk of the SwissTech Convention Centre was overwhelmed twice on Sunday afternoon, which resulted in the entrance been closed for one hour each time. The entirely new approach of this extremely interactive exhibition for the general public offered a quantity of experiences and tests and therefore was seen as a considrable success.

More than 70 partners were present, including 50 public health partners from the French-speaking part of Switzerland. This event exceeded event the highest hope of the exhibitors and the organisers. It was a clear success and demonstrated that the new concept of an interactive exhibition was exactly what the general public were looking for. A survey reveals that the aspect that was most appreciated by the public was was the personal contacts, the tests and the original experiences. In addition 100 conferences and debates were attended by a large number of the public resulting in a packed audiences including in the 450 seat conference theatre. Le event was attended by a general public of all ages, with a high proportion of familes.

The next exhibition will take place in November 2015. The exact dates will be released in January 2015.

http://www.planetesante.ch/Salon2






EPFL Joins Forces with Pharmaceutical Company to Fight Tuberculosis

Lausanne, Switzerland, 25 July 2014

TB CB
Source: Clifton E. Barry III, Ph.D., NIAID, NIH


The pharmaceutical company Nearmedic is collaborating with EPFL to participate in the development of a treatment against tuberculosis. The company bought a license covering the use of the molecule in most countries of the former Soviet Union, where multi- resistant strains are prevalent.

EPFL is one step closer to the development of its antituberculosis agent. In March, the school gave birth to the Innovative Medicines for Tuberculosis Foundation (iM4TB Foundation) with the mission of developing a new and promising treatment against multi-resistant forms of the disease. This unusual approach is necessary to overcome the pharmaceutical industry's lack of interest in this condition that continues to kill more than 1.3 million people per year. The researchers were able to enter into a partnership with the Moscow company Nearmedic. Countries of the former Soviet Union are experiencing a troubling resurgence of the disease in a form resistant to most treatments. This is why the partners have committed to providing the public with effective and affordable treatment.

Called "PBTZ169," the molecule has been very effective in combination with standard therapy, pyrazinamide, as well as with a newer drug, Bedaquiline, approved by the European Union and the U.S. FDA for cases of multidrug-resistant tuberculosis (MDR-TB). According to Stewart Cole, who led the research at EPFL in collaboration with the Bach Institute in Moscow, "these molecules attack different targets in bacteria. By combining them, we drastically reduce the risk that it could mutate into resistant forms."

Accelerating market placement
Nearmedic has more than 2,000 employees in Russia and across the globe. The company is best known for developing a diagnostic system for MDR-TB. The licenses it purchased from EPFL will primarily go toward financing the activities of the iM4TB Foundation. The Russian company will benefit from data produced by the foundation as well as from exclusive rights to the countries of the Commonwealth of Independent States.

"This collaboration will accelerate the placement of our molecule on the market," explains Jean-Yves Gillon, Director of the Development of Drugs at the iM4TB Foundation. "MDR-TB is a serious public health problem, particularly in Russia, and our partners are highly motivated."

A molecule simple to synthesize, an affordable treatment
For now, iM4TB retains the rights for the rest of the world. "We remain open to partnerships with other regions," explains Stewart Cole. "But tuberculosis does not arouse great interest in the industry. For now, this disease affects mostly poor populations, and our priority is to place a treatment on the market at an affordable price."

As it is relatively simple to synthesize, the PBTZ169 molecule can be produced inexpensively. Initial tests showed good compatibility with other TB treatments, and it is expected to be compatible with antiretroviral drugs against HIV. People with HIV are particularly vulnerable to TB bacteria, and cases of cross infections are on the rise.

http://actu.epfl.ch/news/epfl-joins-forces-with-pharmaceutical-company-to-f/






Eighth MM4TB Consortium Meeting

Budapest, Hungary, 30 June - 1 July 2014

The eighth Consortium Meeting (CM8) was hosted by Prof. György Kéri at the Hotel Novotel Budapest Danube in Budapest on 30 June - 1 July 2014.

There were 63 registered participants. All beneficiaries were represented by at least one person with the exception of Cellworks, who were represented by the Project manager.

Prof. Barry Furr OBE, Dr Clifton Barry III and Dr Tanjore Balganesh of the Scientific Advisory Board also attended in order to assess progress.

The prizes for best presentations by young researchers were won by Liliana Rodrigues (UNIZAR). Iain Old (iM4TB) and Beno”t Lechartier (EPFL),

The MM4TB General Assembly unanimously approved the recommendation to hold the next meeting in Bilbao on 8 - 9 January 2014.

MM4TB Budapest
MM4TB researchers at Budapest, Hungary, July 2014





NM4TB project review published on the EC's Horizon 2020 website

Brussels, Belgium, 28 May 2014

TB
Fotolia


Someone dies from tuberculosis (TB) every 15 seconds and 30 million more people will succumb to this deadly bacterium in the coming decade if new treatments are not found. Once known as 'consumption' for the way it 'consumed' the lungs and sometimes other organs, TB is one of the oldest known infectious diseases. Its agent Mycobacterium tuberculosis has already infected a third of the world's population, and this is despite decades of vaccination programmes.

Treatments do exist - Directly observed short course chemotherapy (DOTS) is widely available - but experts now consider them "old, slow and inefficient". What is more, the emergence of multi-drug resistant strains in high-burden countries, especially in Europe, is cause for added concern.

"In fact, we have seen a high correlation between the global HIV epidemic and the spread and resurgence of TB," says Professor Stewart Cole, chief scientist in the EU-funded NM4TB project and head of the Cole Lab at the École Polytechnique Fédérale de Lausanne, Switzerland.

There are good reasons for this shared trajectory. Left unchecked, TB multiplies in the lungs until pneumonia sets in, causing chest pain, prolonged coughing and bloody phlegm. The body's immune system usually prevents the bacteria from spreading to other parts of the body, or people. However, if the immune system is weakened, for example by HIV, the bacterium breaks free of the coating (scar tissue) that isolates it and the disease re-establishes in the lungs and elsewhere - kidneys, bones, spinal cord and brain.

Thanks to significant public and private funding in projects like New Medicines for Tuberculosis (NM4TB) and its successor project which runs until 2016, there is hope. The project team has already identified novel approaches to examine and validate targets for potent new TB drugs capable of cutting treatment time while combatting persistent bacilli and multi-drug resistant strains.

NM4TB ran an ambitious drug-discovery project that combined some of Europe's leading academic TB researchers with a major pharmaceutical company (AstraZeneca) and three small and medium-sized enterprises (SMEs) - all with a strong commitment to discovering new anti-infective agents.

It was a research effort which was truly international in its scope, extending well beyond the borders of Europe. A key role, for example, was played by AstraZeneca India. Based in Bangalore, AstraZeneca's team of scientists provided proof that one particular compound being studied was able to kill the TB bacterium not only in the laboratory but also, potentially, in patients - i.e. in a real 'live' setting.

In the words of Dr Sunita de Sousa, Associate Director, Innovative Medicines, at AstraZeneca in Bangalore:"This was work which required collaboration across continents and borders, across industry and academia. As a multinational biopharmaceutical company, our skills in developing novel, innovative medicines certainly played a role. But above all it was a project which proved the power of collaborative networks in bringing research forward and moving the compound closer to being used to help patients."

The project delivered a comprehensive portfolio of potential and validated targets plus several new, proprietary anti-TB agents in its drug development pipeline. The NM4TB project team discovered benzothiazinones, the most potent drug candidates yet described against TB, while BTZ043 has nearly completed preclinical development so it should reach clinical trials shortly. According to an NM4TB statement, the project results were published in the journal Science.

The continuity of the research for nearly a decade has been a critical factor in building momentum which is culminating in new life-saving drugs: "This is a good funding model to support future drug-discovery programmes for global diseases of poverty, such as TB, which are often neglected by commercial R&D programmes. Subsequent clinical trials of this new drug in people with TB must be fully funded to finally realise the potential of our scientific effort," confirms project partner Professor Philip Butcher of St George's University of London.

In the follow-up project - More medicines for tuberculosis (MM4TB) - the addition of several new academic partners, two SMEs and the Sanofi-Aventis R&D shows a strong and continuing commitment to the discovery of anti-infective agents.

http://www.mm4tb.org/nm4tb/

See Also:

Info-centre






Tuberculosis - EPFL creates a foundation to launch an antibiotic

Lausanne, Switzerland, 12 March 2014

TB
NIAID Creative Commons


Global cooperation to fight a killer disease

Even though tuberculosis kills more than 1.5 million people every year, the market is not cost-effective for pharmaceutical companies. So EPFL is setting up a foundation to release an antibiotic developed in its own laboratories under EU funding.

Researchers from EPFL and the AN Bach Institute in Moscow have discovered a new and extremely promising antibiotic for tuberculosis, especially effective against multi-resistant strains of the disease, which are on the rise in Eastern Europe. The drug, developed as a European FP7 project, has proven very effective against the disease. In an article published in EMBO Molecular medicine, the researchers show that, when combined with other drugs, the new antibiotic, called "PBTZ169", can take down even the most resistant strains of tuberculosis bacteria. Following the publication, the researchers formed the IM4TB Foundation on their campus. Supported by EPFL, the foundation aims to bring the new treatment to the market. This unusual step was taken because traditionally, technology transfer from academia to the pharmaceutical industry doesn't work well with tuberculosis: development costs are too high and the affected countries are often barely able to maintain their own healthcare infrastructures.

With the IM4TB Foundation, EPFL intends to pick up the slack in the limitations of the industrial model. "The development of antibiotics is increasingly expensive and the countries most affected by tuberculosis are still emergent," says Benoit Lechartier, co-author of the PBTZ169 study. "The recent closure of the AstraZeneca research center in India illustrates the extent to which it is difficult for the pharmaceutical industry to invest in infectious diseases."

Human trials in 2015
Located on the EPFL campus, the IM4TB Foundation plans to move onto human trials within a year, in collaboration with the University of Lausanne Hospitals (CHUV).

PBTZ169 shows much promise. It attacks the bacterium's strong point - the cell wall, which forms an impenetrable shield against antibiotics and the patient's immune system. "Our molecule makes the bacterium literally burst open," explains Stewart Cole, director of the study and head of EPFL's Global Health Institute.

A cheap but formidable weapon against resistant strains
The researchers showed that PBTZ169 is extremely effective in tri-therapy, where it is combined with a standard drug, pyrazinamide, and a more recent one, bedaquiline - and both these drugs have already been approved by the EU and the FDA for multi-resistant strains. "This could be the winning strategy", says Cole. "These molecules attack different targets in the bacterium. By combining them, we drastically reduce the risk that it will mutate into more resistant forms."

As a treatment, PBTZ169 has many advantages. It is not expensive to produce, since it is relatively easy to synthesize. Initial tests have shown good compatibility with other anti-tuberculosis treatments and it is expected to be equally compatible with antiretrovirals used to treat AIDS, as HIV-positive individuals are particularly vulnerable to tuberculosis, and cases of cross-infection are on the rise.

This molecule is the culmination of many years of research. The preliminary versions were formidable in the laboratory, where they decimated bacteria in culture. However, their effectiveness in vivo was limited. New technologies like structural biology enabled researchers to redesign the molecule so that it could be more rapidly absorbed. "Thus we were able to improve its pharmacodynamics," explains Cole. "Tuberculosis is often wrongly considered a disease of the past, but in order to fight it, we needed to employ 21st century technologies."

More than 1.5 million deaths per year
Tuberculosis still kills more than 1.5 million people every year. It is uncommon in Europe, although certain countries such as the Ukraine are experiencing a resurgence of patients infected with multiresistant strains. The EU is leading a program that aims to eliminate the disease. The research team at EPFL that developed PBTZ169 received funding from the Seventh Framework Programme (FP7) of the European Commission, in the framework of an international collaboration.

http://actu.epfl.ch/news/tuberculosis-epfl-creates-a-foundation-to-launch-a/






AstraZeneca to shut down R&D site in Bangalore

29 January 2014

I was just informed that some of our collaborators in the MM4TB project will be losing their jobs as AZ closes the site in India.

While I totally understand that no job is for life, there is no stability in pharma anymore and it does not matter if you are in the UK, USA or India it seems.

This hurts on so many levels. As collaborators I have enjoyed many great discussions at MM4TB meetings around Europe with AZ scientists. As someone we work with its distressing, because you wonder who is going to pick up the pieces. AZ were screening their libraries and obviously doing their own projects on TB outside of MM4TB too. Its also sad because the very place that has a TB and malaria problem, is losing a productive lab that could help find future treatments.

The statement "This decision is part of AstraZeneca's broader global business strategy to simplify its research and development footprint and focus resources on three core therapy areas - oncology, cardiovascular and metabolic diseases, and respiratory, inflammation and autoimmunity," is telling - so they are forgetting about the approx 4M people that die annually of TB and malaria or other infectious or neglected diseases ..oops sorry we can make money elsewhere. No but wait "The company will no longer carry out early stage research into neglected tropical diseases, TB and malaria. However, AstraZeneca will continue to progress AZD5847, its phase II programme for TB. In addition, the company's compound library will continue to be made available through open innovation partnerships and AstraZeneca will continue to provide expertise to help advance existing third-party neglected tropical diseases, malaria and TB research programmes for the benefit of patients." what does all that mean? They have a me-too Oxazolidinone that they will pin their money on and will provide their library to existing projects? How though can they provide expertise when they have lost all their experts. What is a third-party neglected tropical disease? Typo or new classification?

A sad, sad day for these scientists and another set back for neglected disease research.

http://www.collabchem.com/2014/01/29/astrazeneca-to-shut-down-rd-site-in-bangalore/






AstraZeneca to shut down R&D site in Bangalore

Raghuvir Badrinath, Bangalore, 30 January 2014

168 research jobs at stake; had during 2012 shed some R&D jobs

AstraZeneca, the global pharmaceutical major, said that it will close its research and development site in Bangalore later this year.

The 'Avishkar R&D Site', employing 168 researchers, was one of the critical centres of AstraZeneca and was involved in the pharmaceutical development and drug discovery research into neglected tropical disease, tuberculosis (TB) and malaria.

"This decision is part of AstraZeneca's broader global business strategy to simplify its research and development footprint and focus resources on three core therapy areas - oncology, cardiovascular and metabolic diseases, and respiratory, inflammation and autoimmunity," a statement from AstraZeneca said.

AstraZeneca started its India R&D operations during 1984 and was operational at the current location since 2003 and its peak strength was 180 researchers.

Pharmaceutical development projects currently carried out at the India site will be transferred either to the company's Macclesfield site in the United Kingdom, or be carried out by external providers..

The Pharmaceutical Development group in Bangalore supported early- to mid-stage clinical development and late-stage life-cycle management across AstraZeneca's core therapy areas.

The company will no longer carry out early stage research into neglected tropical diseases, TB and malaria.

However, AstraZeneca will continue to progress AZD5847, its phase II programme for TB. In addition, the company's compound library will continue to be available through open innovation partnerships and AstraZeneca will continue to help advance existing third-party neglected tropical diseases, malaria and TB research programmes for the benefit of patients.

Employees affected by the changes will start to leave the company at the end of April and the site is expected to close later this year.

AstraZeneca's India commercial organisation and the clinical operations, also based at the Avishkar site, will move to a new location in Bangalore later this year.

AstraZeneca employs more than 1200 people in sales, marketing and manufacturing in India and remains committed to maintaining a significant presence in the country and continuing to deliver innovative medicines to improve the lives of patients. Sudhir Nambiar, site head and Vice President, Pharmaceutical Development, R&D Bangalore said: "We realise this is difficult news for our research colleagues in Bangalore and our priority is to support them over the coming months. We have not taken this decision lightly and acknowledge the excellent work carried out by our people in Bangalore. These changes reflect the company's strategic focus on investing in our core therapy areas and simplifying our R&D footprint."

Dr T S Balganesh, a distinguished scientist, was one of the key catalysts of this centre. Balganesh came on board during 1987 as Scientist (Project Leader) Diarrhoeal diseases and later grew in strength to be the VP - Discovery, R&D Bangalore and Executive Director of the centre between 2005-11 before moving on to join CSIR Centre for Mathematical Modelling and Computer Simulation (C-MMACS), under the Government of India.

During 2012, AstraZeneca had said that around 15 scientists were affected due to the global right-sizing which was being rolled out across its global operations.

Senior R&D professionals in the sector indicated that this move by AstraZeneca to shut down the centre in Bangalore may be indicative of the reflection of the tough situation which pharmaceutical industry is going through globally. "Many of them are aligning with biotechnology companies to fuel the drug pipeline and this will have more momentum," a senior R&D professional noted.

AstraZeneca further noted that the decision to shut the Bangalore centre is in no way a reflection on the excellent work or the performance of the scientists and other experts at the site.

"Bangalore is renowned for its energy, high quality and productivity, and employees should be deeply proud of what they have accomplished. This decision is in no way related to any local issues or changes to the regulatory environment or to the performance of our R&D teams in India, which has been of high quality," AstraZeneca noted.

  • AstraZeneca opened R&D operations during 1984

  • The site will be shut later this year

  • 168 research jobs at stake

  • Facility worked extensively on TB & malaria

  • The compound library will continue to be made available through open innovation partnerships


http://www.business-standard.com/article/companies/astrazeneca-to-shut-down-r-d-site-in-bangalore-114012901153_1.html






Seventh MM4TB Consortium Meeting

Cambridge, United Kingdom, 6 - 7 January 2014

The seventh Consortium Meeting (CM) was hosted by Prof. Chris Abell and Professor Sir Tom Blundell at Queens' College at the University of Cambridge on 6 - 7 January 2014. Prof. Barry Furr OBE and Dr Tanjore Balganesh of the Scientific Advisory Board also attended in order to assess progress.

MM4TB Cambridge
MM4TB researchers at Cambridge, UK, January 2014