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The latent threat of tuberculosis
Chemistry World ^ | 15 August 2012 | Clare Sansom

Posted on 02/03/2013 12:33:41 AM PST by neverdem

Although TB was close to being eradicated in the developed world, it is a major problem in developing countries. With drug-resistant strains on the increase, Clare Sansom outlines the latest in the fight against this killer disease

From a historical viewpoint, what is the world’s most deadly infectious disease? Tuberculosis (TB) must be one of the strongest contenders. The disease that the seventeenth-century writer John Bunyan described as ‘the captain of all the men of death’ is still rightly feared today. Despite some recent progress, the latest figures released by the World Health Organisation (WHO) show that there were an estimated 8.8 million cases of active tuberculosis and 1.4 million deaths from the disease in 2010.

But the current WHO guidelines for managing tuberculosis describe it as ‘treatable and curable’, so why is it still such a worldwide problem? Control of any infectious disease can be divided into three areas: prevention (including vaccination), diagnosis and treatment, and progress in each of these areas has been painfully slow for most of the 130 years since TB’s cause was discovered. The only widely used vaccine against TB has been around for 90 years, and no new drugs against the disease have entered the clinic for over 40. Cases are too often misdiagnosed or missed altogether.

A TB bacterium being engulfed by a macrophages. Credit: Science Photo Library

A TB bacterium being engulfed by a macrophages. Credit: Science Photo LibraryThe eponymous bacterium that causes TB, Mycobacterium tuberculosis, was discovered by Robert Koch, who also formulated the postulates that bear his name for establishing the cause of an infectious disease. It is an unusual beast, much slower to grow than most bacteria, and with a characteristic thick coat principally made of mycolic acids. It infects the lungs of its human host, where it is taken up by macrophages – the cells that remove debris and pathogens by engulfing and digesting them. Unfortunately, TB bacilli can live within them for many years without causing the active disease and it has been estimated that about a third of the world’s population carry this ‘latent’ form of TB.

Complex therapy

Tuberculosis has historically been associated, under its former name of consumption, with a number of notable literary and intellectual figures. Keats and Chopin suffered from the disease, as did George Orwell, who used some of the royalties from Nineteen Eighty-Four to import streptomycin – the first drug to prove at all effective against tuberculosis – from the US. Nowadays, however, ‘the burden of TB is carried by the most vulnerable’ according to Mario Raviglione, director of the Stop TB Department at the WHO. This refers to the world’s poorest people, who live in crowded, unsanitary conditions, and often suffer from other conditions that increase the odds of latent disease becoming activated. HIV is the most important of these: the ‘deadly synergy’ between AIDS and tuberculosis has often been described in the literature. Latent TB is over twenty times more likely to become active in people who are HIV positive than in those who are not.

The current treatment regimen for drug-sensitive tuberculosis is long and complex, involving four drugs from different chemical classes. Patients are treated with isoniazid, rifampicin, pyrazinamide and ethambutol for two months, then just isoniazid and rifampicin for a further four. Understandably, many people find this regimen difficult to follow, especially as each of these drugs has side effects: isoniazid can cause neuropathy, which is exacerbated in people with HIV, and rifampicin can be toxic to the liver. The WHO therefore recommends the DOTS (directly observed therapy, short course) strategy where a healthcare worker directly observes patients taking their medication. This has now been widely, although not universally, adopted, but it is hardest to maintain in the poorer countries and difficult conditions where tuberculosis flourishes most easily.

The complex nature of the ‘standard’ tuberculosis therapy is only the tip of the iceberg of problems with treating TB. Multi-drug resistant (MDR) tuberculosis, in which the bacteria are resistant to at least isoniazid and rifampicin, has now been identified in almost every country. Patients diagnosed with this form of the disease have to endure two-year courses of treatment with toxic second-line drugs; the cost of treating a single patient with MDR-TB in the UK has been estimated at £50,000–£100,000. Extensively drug resistant tuberculosis, which responds to even fewer drugs, has also been widely reported, as has a form of totally drug resistant TB in countries as diverse as Italy, Iran and India.

Politics and money

The political will to tackle tuberculosis, along with other infectious diseases of the poor, may have reached an all-time low in the years before the AIDS epidemic brought infection back into the centre of public consciousness. Since then, and more particularly since the turn of the millennium, TB has moved closer to centre stage. It is the only ‘other disease’ to be mentioned explicitly in the targets set for the UN’s Millennium Development Goal 6 (to ‘combat HIV/AIDS, malaria and other diseases’). During the last ten years, governments, companies and private philanthropists have channelled huge sums by historical standards into tuberculosis prevention and care through the Global Fund to Fight AIDS, Malaria and Tuberculosis.

This fund, however, did not escape the effects of the global financial crisis: the eleventh and most recent funding round had to be cancelled in November 2011 due to a shortfall in donations, most markedly from governments. This threatened to derail much excellent work until the cause was taken up by, among others, the All-Party Parliamentary Group on Global Tuberculosis, a group of UK politicians with an interest in TB. ‘Even in these austere times, we managed to persuade the UK government to double its contributions to this fund, and others are doing the same, so with any luck it should soon be back on track’, says Simon Logan, policy adviser to this group.

The Global Fund has no remit to fund the discovery and development of diagnostics, drugs or vaccines. Much of the recent progress that has been made in these areas – and since the turn of the millennium this has been considerable – has been driven by the academic and small biotech sectors, and by developments in genomics. The tuberculosis genome was published in 1998, only three years after that of the first free-living organism. It is large for a bacterial genome, with four million base pairs and 3959 protein-coding genes. About 250 of these are involved in the metabolism of fatty acids, including those comprising its complex cell wall.

Diagnosis and drugs

The standard method for diagnosing TB  for a long time was a chest x-ray. Credit: Gustoimages/Science Photo Library

The standard method for diagnosing TB for a long time was a chest x-ray. Credit: Gustoimages/Science Photo LibraryBut all the money in the world will not produce a cure for tuberculosis if interdisciplinary science fails to deliver. For tuberculosis (or any disease) to be treated effectively, it must first be correctly diagnosed. Ruth McNerney from the London School of Hygiene and Tropical Medicine, UK, explains the extent of the problem: ‘We still don’t know exactly how much TB there is in the world. We estimate that about a third of people don’t get diagnosed, so they’re not treated, and, of course, they remain infectious.’ Until very recently, the main method for diagnosis involved a chest X-ray followed by a difficult culture of the slow-growing bacterium from a sample of blood or sputum.

The first molecular system for the diagnosis of TB, Cepheid’s GeneXpert, was endorsed by the WHO at the end of 2010. This simple-to-use PCR-based platform can return a diagnosis of TB in no more than an hour. Its only real disadvantage is its high cost; even at the latest subsidised rate of $10 per test, it is unaffordable in many developing countries. ‘Technical improvements and competition from rival companies will bring the price down further, but it will probably always remain out of reach of some who need it,’ says McNerney. She is also concerned that diagnosis is still crude: ‘There is an urgent need for more biomarkers. We need to be able to look at a whole panel of antibodies and antigens at once, to distinguish between latent and active TB and to tell how drug resistant a sample is,’ she adds.

After diagnosis comes treatment. Drug discovery programmes typically focus on a specific unmet medical need, and tuberculosis can offer many of these. It is clear that a wider range of drugs is needed, particularly to combat resistant strains. Further priorities are shorter, simpler treatment regimens for TB that is not yet resistant to drugs, which would be less toxic and easier for patients to follow, and more appropriate treatments for co-infections with HIV. Finally, there are no drugs at all for latent TB infection: such a drug, which could prevent both symptomatic illness and the spread of the disease, could be almost as effective in controlling it as a vaccine. In all cases, cost will always be a serious concern. ‘We need to develop new drugs, but we also want them to be on the market and affordable in countries with a high TB burden,’ says Logan.

After the publication of the first bacterial genome sequences, much early-stage drug discovery was target-based. Many researchers used bioinformatics and structural biology to select and elucidate the details of the proteins considered both essential for bacterial metabolism and relatively easy to be inhibited by small-molecule drugs. Recently, however, the use of phenotype-based assays to select candidate molecules without prior knowledge of their mechanism of action has made something of a comeback. ‘The target-based approach has generally failed to deliver [in drug development for TB]’ says Geoff Coxon, a medicinal chemist from the University of Strathclyde, Scotland and Tuberculosis Drug Discovery UK.

The SPOTi screening technique can test 2000 potential anti-TB drug molecules in six months

The SPOTi screening technique can test 2000 potential anti-TB drug molecules in six monthsMany scientists advocate a two-pronged approach incorporating both target-based and phenotype-based methods, Sanjib Bhakta from Birkbeck, University of London UK, among them. His group has developed a fast phenotypic screen – SPOTi – that can evaluate the potential anti-tubercular properties of as many as 2,000 molecules in six months. They have also published structural studies of the Mur ligase family of enzymes that are essential for the formation of the mycobacterial cell wall. ‘We are collaborating with medicinal chemists in University College, London, to develop hit molecules from both these screens into leads, and GSK is already interested in taking really promising molecules into clinical trials,’ Bhakta says.

Showing promise

The later-stage drug development pipeline is finally beginning to fill with promising candidate drugs. Two molecules with different novel targets – bedaquiline, developed by Janssen (now part of Johnson & Johnson) and Otsuka’s delamanid – are now entering Phase III clinical trials.

Bedaquiline, discovered through a phenotypic screen and believed to be active against both drug-sensitive and drug-resistant TB, has an unexpected target: mycobacterial ATPase. ‘Nobody would have ever picked bacterial ATPase as an interesting target for anti-TB drugs, because of its perceived similarity with human mitochondrial ATPase,’ says Koen Andries, a distinguished research fellow at Janssen. ‘Despite this similarity, there are a few key amino acid differences in the enzyme active site, and these are enough to lead to drug specificity. This is a lesson to drug developers: a [bacterial] protein should not be excluded as a drug target because it has a human homologue.’ Janssen has taken the molecule through Phase II clinical trials against MDR-TB, with trials against the drug sensitive disease being undertaken by the non-profit Global Alliance for TB Drug Development.

Otsuka’s molecule, an imidazooxazole, is also showing particular promise against drug resistant strains of tuberculosis. It blocks the synthesis of two mycolic acids that are necessary in mycobacterial metabolism. ‘Phase II trials have shown that adding delamanid to the standard treatment for MDR-TB can increase the response rate significantly,’ says Larry Geiter, vice president for global clinical development at Otsuka.

A Phase III trial of delamanid in MDR-TB has just started, and the company filed a new drug application to the European Medicines Agency for this drug in MDR tuberculosis in December 2011. In July 2012, Johnson & Johnson filed an new drug application for bedaquiline with the US Food and Drug Adminstration against the same condition. If or when either application leads to a full registration, that drug is likely to be the first novel anti-tubercular to enter the clinic in almost half a century. There is still a long way to go, however. ‘Late stage clinical trials for tuberculosis are long and complex, and require patients to be recruited internationally; it is particularly difficult to find enough patients with definitively diagnosed drug-resistant TB to fit a trial protocol,’ says Patrick Phillips, a senior statistician at the MRC Clinical Trials Unit in London. ‘They will therefore often be run as collaborations, sometimes involving both the public and private sectors.’

These are exciting times for tuberculosis research and drug development, and there are grounds for optimism that the long wait for new medicines will soon be over. Fourteen years after the publication of the TB genome, it is possible to imagine a time when the cocktail of drugs to treat an individual tuberculosis patient might be tailor-made using knowledge of the genome of the bacteria infecting them. This ‘personalised medicine’ for tuberculosis patients should become technically possible before very long, but it will remain expensive: ‘Investment in technology transfer will be needed to make sure that new diagnostics and drugs reach those who need them most, the most vulnerable,’ says Raviglione.

TOPICS: Health/Medicine; Science
KEYWORDS: latenttb; microbiology; tb; tuberculosis

1 posted on 02/03/2013 12:33:52 AM PST by neverdem
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To: neverdem

This is good information about detection, forms of disease and treatments. However, is there any exhaustive study into the sources (i.e., people/country) sources of this and other deadly heretofore-thought-erradicated diseases?

It just seems to me that as each year goes by in this country, we hear of untreatable forms of TB, flesh eating diseases, waterborne microbe infections, and other diseases like smallpox, bubonic plague and the like.

Myself, I can’t help but think that there is a valid connection between the re-emergence of these diseases and the influx of illegal aliens. Can’t prove it, but I believe it so.

2 posted on 02/03/2013 4:07:41 AM PST by Gaffer
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To: neverdem
"Open borders. Herd immunity. Luring infected immigrants.
Zero testing. Homeland concern abdication.
What difference does it make?"

3 posted on 02/03/2013 4:29:32 AM PST by Diogenesis (De Oppresso Liber)
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To: neverdem

Had it. 40 years ago. Was locked in a ward. They finally figured out it was atypical, and not a contagious type.

4 posted on 02/03/2013 4:59:18 AM PST by Dr. Bogus Pachysandra ( Ya can't pick up a turd by the clean end!)
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To: Gaffer

When our son was young, I was hesitant to get all the vaccinations docs recommended. She said simply, ‘Then keep him out of WalMart and other places where you’ll find 3rd-world immigrants.’

5 posted on 02/03/2013 5:34:40 AM PST by bboop (does not suffer fools gladly)
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To: neverdem

We have the AIDS population to thank for the resurgence.

6 posted on 02/03/2013 6:39:34 AM PST by rashley (Rashley)
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To: neverdem

A few things about TB:

The most common variety is still “ordinary” TB, but there is also resistant TB (RTB); multiple drug resistant TB (MDR-TB); extremely drug resistant TB (XDR-TB); and in India they found a type that was totally drug resistant (TTB), but it killed everyone infected by it, quickly, so it may have defeated itself.

As a rule of thumb, MDR-TB is very hard to treat, has a high mortality rate and needs hospital isolation. XDR-TB is almost always lethal, and you are in isolation until you die, then the entire room is sterilized. TTB kills so fast that treatment is not an option, just cremation.

TB is very hard to treat for an odd reason. Most bacteria reproduce about every half hour, but TB only reproduces about two or three times a day.

The typical TB (tine) test, just determines if you have been exposed to the disease. Exposure means you are infected, but the disease is still passive, waiting as long as a decade or two before going active.

With exposure, you need to take some drugs for a minimum of six months.

A positive tine test is followed up by a blood test, to see if your infection has gone active. If that is the case, then you need to take different drugs for several years.

Comparatively speaking, TB is very similar to Leprosy, belonging to the same genus, though different species.

TB is rather odd in that it can attack almost every organ in the body: the brains, kidneys, muscles, heart, bones and spine, but most often the lungs.

The second stage of the disease is manifested by destruction or “consumption” of the tissues of the affected organ. When the lung is affected, it results in diminished respiratory capacity, associated with other symptoms; when other organs are affected, even if treated adequately, it may leave permanent, disabling scar tissue.

Often TB patients are confined to wheelchairs when their spine is afflicted. Some go insane, some become hypersexual or hypercreative, some look normal and healthy and then keel over dead.

It is both unpredictable and unnerving, and the terror its epidemics inflicted in Europe and America resulted in the Gothic period, and much horror fiction and the obsession with morbidity. Likewise, the popular “Victorian look”, gaunt and pale, was an effort to look like the person had TB.

In the US, many of those afflicted moved to the desert southwest, which had many TB sanitariums, recognizable for their smokestacks, because they burned both their mattresses and linens.

With antibiotics, TB had been almost wiped out in the US. But no more.

7 posted on 02/03/2013 7:53:09 AM PST by yefragetuwrabrumuy (Best WoT news at
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To: Mother Abigail; EBH; vetvetdoug; Smokin' Joe; Global2010; Battle Axe; null and void; ...
FReepmail me if you want on or off my combined microbiology/immunology ping list.
8 posted on 02/03/2013 11:06:19 AM PST by neverdem ( Xin loi min oi)
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To: neverdem


9 posted on 02/03/2013 11:19:12 AM PST by vetvetdoug
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To: yefragetuwrabrumuy

I had a patient with Pott’s disease, TB of the spine, when I was a resident in the mid 1990s. She presented in the ER unable to walk. IIRC, she already had a CT or MRI as an outpatient that suggested Pott’s. She was able to walk again after about a month of treatment.

10 posted on 02/03/2013 11:27:05 AM PST by neverdem ( Xin loi min oi)
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To: bboop

“.... other places where you’ll find 3rd world immigrants”.

Our pediatricians now check for TB very often. Why? Well, our country has so many 3rd world people everywhere. Schools, malls, shopping centers, grocery stores and fast food places. If I recall correctly, immigrants were checked for diseases such as TB (Ellis Island, for example). Now with air travel and folks just walking right in.. the threat of these diseases have increased. Scary stuff!

11 posted on 02/03/2013 11:49:26 AM PST by momtothree (Thanks for the memories, Ray Ray!)
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