New methods to fight tuberculosis

The global tuberculosis trend is spreading and new strains that are resistant to any drug are emerging and appearing. To fight back, biologists apply a variety of innovative methods for drug development

By Clifton A. Berry III and Maya Cheung

Smallpox, smallpox, polio, AIDS - the annals of the world are full of diseases that shaped the social climate of their time, defined the limits of scientific and medical knowledge, and killed the great creators prematurely. But it seems that one disease accompanies humanity more than any other disease: tuberculosis. Fossil evidence shows that tuberculosis haunted humans more than half a million years ago. No one is immune to her. It hurt the rich and the poor, the young and the old, the brave and the hidden. It is enough for a person infected with the disease to cough, spit or even talk, to spread the bacteria that causes it.

Tuberculosis, known as TB, is currently ranked second after AIDS in the rate of fatal infections in the world. It takes the lives of two million people every year, even though the drugs available today are able to cure almost all patients. In fact, the problem is that many people do not have access to drugs, and even those who are able to obtain them are unable to comply with the long-term treatment regimen.

On top of that, the evolution of tuberculosis is faster than the pace of drug development. In recent years, researchers have noticed that there has been an alarming increase in the number of people who have contracted tuberculosis that is resistant to more than one of the most advanced drugs used to treat the disease. Even more frightening is the knowledge that strains have begun to appear that are resistant to all antibiotic drugs, down to the last of them.

The disease is especially devastating in the developing countries, where 90% of the patients are found and 98% of the deaths occur. Apart from the indescribable suffering and sorrow that TB causes, it damages the entire economy. Since 75% of the dead are between the ages of 15 and 54, tuberculosis robs the world's poorest countries of an annual income estimated at 12 billion dollars - 4% to 7% of the gross national product of some of them. Moreover, the disease forces these nations, struggling for their existence, to divert precious resources from other important areas to the health system. But the developed world would be mistaken if it thought it was safe: even though the extent of the disease there is relatively small, the situation could change if a particularly resistant strain of the bacterium is absorbed into the population.

Even if the situation is gloomy, we have reason to hope. State-of-the-art biomolecular methods allow researchers to study the complex interactions between the tuberculosis bacterium and the human body in unprecedented detail. The resulting insights make it possible to develop diagnostic tests and innovative drug treatments.

Short-lived success

German physician Robert Koch first discovered the rod-like bacterium Mycobacterium tuberculosis, or Mtb, which causes tuberculosis. The bacterium exists in two forms: active and latent. If you get infected in the hidden form, the immune system prevents the bacteria from multiplying and damaging the tissues. Those who are infected in this way do not show symptoms and do not infect others with the disease. Latent Mtb bacteria may exist for months, years and even decades without dividing and without making their host sick. About 90% of those infected with the bacteria will never develop active tuberculosis. However, 10% will develop the active form, especially those with a weakened immune system, such as children, AIDS patients and chemotherapy patients.

In people infected with active tuberculosis, the bacteria overcome the immune system, and they multiply rapidly, spread in the body and attack its organs. The tuberculosis bacterium is an aerobic bacterium, meaning it prefers oxygen-rich environments, so it tends to attack the lungs. Indeed, about 75% of patients with active tuberculosis have pulmonary strains. When the bacteria multiply, they destroy the lung tissue and usually cause a severe cough, chest pain and coughing up blood. Other organs are also vulnerable. In fact, active tuberculosis can attack almost any organ in the body. A bacterium found in children's bodies invades the spine and causes high fever and a state of systemic shock, known as meningitis. Without treatment, half of the patients with active tuberculosis will die, most of them due to the destruction of the lungs.

About 100 years ago, society had no way to fight tuberculosis other than limiting its spread by isolating patients in hospitals. At that time, tuberculosis was common even in places where the rate of the disease is low today, such as North America and Europe. Scientists achieved their first achievements in the fight against the disease in 1921, when the French vaccine researchers Albert Calmet and Camille Guerin from the Pasteur Institute developed a compound and began to vaccinate the public (at first it was believed that the compound, known as BCG, was effective against tuberculosis that attacks adults and against tuberculosis in children. But after a comprehensive series of tests it became clear which is consistently effective against only the most severe strains of childhood TB).

25 years later, the American microbiologist Zalman Waxman developed streptomycin, which served as the first effective drug against tuberculosis, although its use involved several side effects. Waxman's achievement opened the door to the rapid development of antibiotic drugs that covered the weaknesses of streptomycin in the 50s.

These developments brought an end to the era of sanatoriums and significantly lowered the TB rate in countries with the capital and infrastructure needed to deal with the problem. Until the 70s, many experts believed that tuberculosis had been completely eradicated. But in fact it was only then, when international travel gained momentum, that the really big epidemics began. What worsened the situation was that those who were going to be hit the hardest were those who had a particularly hard time dealing with the disease: the inhabitants of the poorest countries, who a short time later had to deal with a new and expensive killer - the AIDS virus.

Today, more than half a century after the debut of anti-tuberculosis drugs, the World Health Organization estimates that a third of the world's population (more than two billion people) carry the tuberculosis bacteria in their bodies. Eight million of these carriers, on average, will develop active tuberculosis each year, and each of them will infect ten to fifteen people and continue the epidemic.

The picture becomes even scarier if you take into account the increase in the rate of AIDS patients. The chance that TB carriers who are also AIDS carriers will develop active tuberculosis is 30 to 50 times higher than the chance of TB carriers who are not AIDS carriers to develop such tuberculosis. The reason for this is that the AIDS viruses, HIV, damage the immune system and disrupt its ability to control tuberculosis. In fact, tuberculosis is the main cause of death among AIDS carriers. It kills one in three carriers worldwide and one in two in sub-Saharan Africa, where treatment is particularly difficult to obtain. But even if AIDS carriers receive anti-tuberculosis drugs, their health will most likely deteriorate. This is because dangerous inter-drug effects caused by a combination of treatment against retroviruses and drugs from the first level of treatment against tuberculosis will force them to suspend the treatment against AIDS until the tuberculosis is under control.

The last challenge

But the most worrying aspect of the current epidemic is perhaps the worsening problem of the tuberculosis bacterium's resistance to antibiotics. To understand how this difficult situation came about, you need to know how tuberculosis is treated. The treatment accepted today was developed in the 60s. It requires a demanding regimen of taking four first-line drugs created in the 50s and 60s: isoniazid, ethambutol, pyrazinamide, and rifampin. Patients who wish to follow this regimen as required should take an average of 130 doses of medication, preferably under the direct supervision of a healthcare worker. This combination is very effective against active, drug-responsive TB as long as patients are disciplined and complete the six to nine month course of treatment.

Drug-resistant strains develop when patients do not complete the entire process, either because they start to feel better or because the drug supply is interrupted for some reason. Inconsistent use of antibiotics gives bacteria time to evolve and develop resistance. If a resistant strain has developed in one person's body, the carrier may spread the resistant version to others. (For this reason, there are authorities who believe that it is better not to give treatment at all than to give incomplete treatment.)

The World Health Organization reports that strains of bacteria resistant to the two most common drugs in the current treatment regimen - isoniazid and rifampin - are involved in almost 5% of the approximately 8 million cases of tuberculosis that erupt each year. It is possible to treat most patients with this type of tuberculosis, which shows multidrug resistance and is known as MDR-TB, but the treatment lasts up to two years and requires strong drugs, the second level of treatment, which cause severe side effects. Furthermore, MDR-TB treatment is up to 1,400 times more expensive than standard treatment. And since most MDR-TB patients live in poor countries, this expensive treatment is not possible at all. It is estimated that due to the high price and failure to diagnose resistant tuberculosis, only 2% of all MDR-TB patients in the world are treated correctly.

And worst of all, in recent years, health surveys have revealed an even more serious threat: tuberculosis with extensive drug resistance - XDR-TB. This type of TB, which made headlines in 2006 after an outbreak in KwaZulu-Natal, South Africa, is resistant to virtually all of the most effective drugs in advanced second-line therapy. Although XDR-TB is less common than MDR-TB, the possibility that XDR-TB will develop and spread is a threat wherever second-line TB treatment is used. World Health Organization data show that until June 2008, resistant tuberculosis was detected in 49 countries. This is the minimum number because only a few countries have laboratories capable of diagnosing XDR-TB.

The medicine pipe is blocked

To say that scientists were wrong in assuming that the first-rate drugs developed in the 50s were enough to fight TB would be an understatement. Since the majority of TB patients are concentrated in the world's poorest countries, the big pharmaceutical companies had no incentive to invest their best money in developing new drugs. Even today, the prevailing opinion in the large pharmaceutical corporations is that the cost of drug development, 115 to 240 million dollars over seven to ten years, is much higher than the expected profit from the potential global market for anti-tuberculosis products.

But thanks to government and private programs, including programs by charitable organizations such as the Bill and Melinda Gates Foundation, considerable efforts are being made to create antibiotic drugs against tuberculosis - both to fight drug-resistant bacteria and to shorten the duration of treatment for patients infected with the usual bacteria.

Thus some promising substances are now in early stages of clinical trial. One such agent, SQ109, inhibits cell wall synthesis. Not long ago, the first phase of the clinical trials, testing the safety of using the substance, ended. One drug candidate, PA-824, is an agent capable of attacking TB bacteria both in their actively dividing phase and in their latent phase, where they multiply slowly. It is hoped that this material will significantly shorten the time needed to treat the disease. The substance PA-824 is in the second phase of clinical trials, and its effectiveness is now being tested.

Unfortunately, the chances that these two candidates will succeed are slim: past experience shows that less than 10% of the antibiotic substances tested in the first stages of clinical trials are approved. This low success rate is mainly due to the outdated logic used to discover these drugs. 15 years ago it was common to develop a new antibiotic according to a simple recipe: these are the enzymes essential for the survival of the bacterium that do not have corresponding enzymes in humans; compound libraries were scanned for possible inhibitors of these enzymes; Chemical derivatives of these inhibitors were prepared in the laboratory; And if possible adapt the properties of the materials to the requirements of the drugs, for example the ability to pass from the intestines to the blood circulation. However, even the big pharmaceutical companies, the artists of drug development to treat almost every disease, failed miserably in producing new antibiotics using this approach.

The battlefield against TB is thus littered with the corpses of failed drug candidates. Many of these compounds were substances effective in inhibiting specific important enzymes in bacterial cells. But sometimes substances that succeeded in inhibiting isolated enzymes failed the test in whole bacterial cells, and sometimes substances found to be effective against whole bacteria in vitro missed the mark when tested in infected animals. Tuberculosis is perhaps the most extreme example of the disturbing gap between the antibiotic abilities in vitro and the activity of these substances in the living body. Researchers usually have no idea why candidate substances fail as drugs. The heart of the problem is that bacteria are independent life forms that survived during evolution due to their adaptability and ability to respond to external threats. Like modern fighter jets, they have a wide variety of reserve systems, bypasses, fail-safe devices and emergency backup systems. As the character played by Jeff Goldblum in the movie "Jurassic Park" says: "Life finds a way." Until we truly understand the complexity of the interactions between the tuberculosis bacteria and the human body, the drugs against the disease will not be within our reach. The good news is that we are making good progress on this front.

Insights from the fields of "Omics"

The decisive turning point in our TB education series was in 1998. Then the determination of the DNA sequence (DNA), or the genome, of the tuberculosis bacterium was completed, a project in which one of us (Berry) participated. This sequence and sequences of related organisms provided a treasure trove of insights. And perhaps most important of all - the results showed that so far the scientists have tested in vitro only one third of the many enzymes and reactions necessary for the survival of the tuberculosis bacterium in the human body. We learned, for example, that the tuberculosis bacterium sets aside a huge part of its genome to encode proteins that produce and break down fats. This suggests that some of these proteins may serve as drug targets. Analysis of the tuberculosis genome also suggested that the bacteria are absolutely capable of living without air, contrary to popular opinion. This hint has since been confirmed. Under such anaerobic conditions, the bacteria's metabolism slows down, and thus, naturally, its sensitivity to antibiotics is reduced. Directing the drugs to attack the metabolic mechanisms that remain active in these circumstances is one of the most promising approaches to shortening the duration of treatment.

Translating the information we gathered from the genome into discoveries that will help save the lives of those infected with tuberculosis is neither simple nor direct. Recently, however, researchers have used this information to make significant progress in developing tests to diagnose the disease. The diagnosis is sometimes complicated due to the effects of the childhood vaccines that are given to more than half of the toddlers worldwide. The vaccine component includes a strain of tuberculosis bacteria that has lost its ability to destroy but is still able to stimulate the child's immune system against tuberculosis bacteria, and the standard test for diagnosing tuberculosis is annoyingly difficult to distinguish between the harmful strain and the reservoir strain. The test results of a person infected with tuberculosis are therefore identical to the results of a vaccinated person.

When the gene sequence of the tuberculosis bacterium was determined, scientists from Seattle discovered that the DNA of the strain used for the vaccine was missing a long segment. After a short time, research groups from the Pasteur Institute, the Albert Einstein College of Medicine and the University of Washington showed that the missing genes are essential for causing the disease. The missing segment in the depot strain thus provided the researchers with a method to improve the assay. The researchers believed that developing a test that would reveal an immune response only to factors in the bacterium that causes the disease that are missing in the reservoir strain would make it possible to differentiate between people who have contracted tuberculosis and those who have been vaccinated against it. In fact, just such a test was developed and approved for use by the US Food and Drug Administration in 2005, and many studies have confirmed its accuracy. Unfortunately, the test is expensive and its use is limited to the first world only.

The TB bacterium genome is not the only new source of data providing insights into the bacterium's possible vulnerabilities. Scientists today are able to study various components and processes in the cell, including the total number of proteins in the cell (a field called "proteomics"), the amount of messenger RNA (the templates according to which proteins are produced) produced by each gene ("transcriptomics"), the intermediate and end products of metabolism in the cell ("metabolomics"). Although the researches about these areas are still in their infancy, they are already bearing fruit. In November 2008, an article was published in the journal Science, of which Berry was one of the authors, in which it was reported that treatment of tuberculosis with the substance PA-824 caused the transcriptome of the bacterium to react exactly as it would have reacted if it had been poisoned with potassium cyanide. This discovery served as an essential clue that when the bacterium processes the drug as part of its metabolism, it releases nitrogen monoxide, a molecule normally used by the immune system of human cells for protection. Armed with this knowledge, we and other researchers are now synthesizing compounds that stimulate the release of amounts of nitric oxide greater than those stimulated by PA-824, so we anticipate that the compounds will serve as a more effective drug against the TB bacterium.

To complete all approaches, structural genomics aims to discover the three-dimensional structure of each protein in the tuberculosis bacterium. This work could help in identifying the unknown roles of many tuberculosis proteins and in the design and preparation of drugs aimed at attacking certain sites in important proteins. This research approach is so promising that a global consortium of 17 countries has chosen to focus all its efforts on the structural genomics of the tuberculosis bacterium. So far, the consortium has helped determine the structure of about 10% of the bacteria's proteins.

Another branch of "omics" worth mentioning is chemical genomics, a field of research that was created not long ago and in fact reverses the accepted order of operations in drug discovery. Instead of starting the search for a compound that will inhibit the action of a protein with a known activity, the researchers begin the search for a compound that has a known desired property, such as the ability to inhibit the division of tuberculosis bacteria in cell culture. Then the researchers look back and look for the bacterial enzyme that the substance damages. The compounds may be artificial molecules prepared in the laboratory or substances isolated from plants, bacteria and even animals. The first material tested is only used to uncover vulnerable enzymes or biological processes, which the scientists can then identify as targets for drug development.

This approach is attractive because it allows us to harness natural selection in our efforts to curb the TB bacteria. Before this bacterium and its relatives from the mycobacteria family found such convenient hosts in humans, they inhabited environmental niches where they had to compete with many other bacteria for food and maintain a constant arms race. Bacterial ecosystems have thus undergone many rounds of natural selection, and usually other bacteria have succeeded in developing methods to contain the mycobacteria. The rich diversity of the bacteria infesting these ecosystems proves their success. The hope is that scientists will be able to take advantage of this amazing arsenal of weapons developed by the competing bacteria. The identification will be made possible through modern "omics" methods, which will identify the defense molecules, locate those active against tuberculosis, and focus on their target molecules within the tuberculosis bacterium - then we may be able to discover completely different types of drugs. We can choose the factors capable of destroying the entire system of the bacterium that causes the disease and not just blocking a single process, which the tuberculosis bacterium can probably bypass.

A model bacterium

In order to reap all the fruits of the "Omics" revolution, we must use information technology tools that will make it possible to introduce a logical order in the extensive data sets created by the "Omics" experiments. In fact, the development of such tools has become a field of research in itself, called bioinformatics. Only through these tools will researchers be able to overcome another obstacle in drug development, which is the obstacle of emergent properties, i.e. modes of behavior of biological systems that cannot be predicted based on the biochemical properties of each of the components of these systems.

If we ask an example from the field of neurology, consciousness is considered an emergent feature of brain biochemistry. One of the features emerging in test tube experiments with the tuberculosis bacterium is the tendency of the bacteria to create "wicks" - arrays that twist around each other similar to ropes. These fuses are formed due to the complicated interaction of molecules found on the surface of the bacteria, and it is impossible to predict their formation based on the properties of the molecules involved. Similar interactions occur between the surface molecules of the bacteria and between the cells of the immune system in the human body. These actions create granulomas: large clumps of human cells and bacteria that the drugs find very difficult to penetrate. The formation of these nodules is an emergent feature of the interaction between the TB bacteria and the host.

With the help of bioinformatics, we hope to find out how all 4,000 genes of the tuberculosis bacterium, the proteins corresponding to these genes and the metabolic by-products of the bacterium react to a new drug when treating the tuberculosis bacterium in vitro. Moreover, in the last ten years we have begun to complete the exact picture of the action of bacteria in the bodies of tuberculosis patients and not only in a test tube. The ultimate goal is to replicate the TB bacteria on a computer. That is, to create a computer simulation of the bacterium that behaves exactly like the real bacterium in the body. The importance of such an achievement cannot be understated, because it will allow researchers to accurately predict which components in the bacterial cell are suitable to be used as a target for drugs and which of the candidate substances to be used as a drug will damage these targets with maximum efficiency.

To achieve this goal, the scientists will have to study in detail all the biochemical pathways (series of chemical reactions) of the bacterium and identify additional properties that arise as a result of the operation of these pathways. The task is enormous: we still don't know what about a third of the TB proteins do, and of course not what pathways are associated with them and what nascent properties they stimulate. But according to the rate of research progress today, we are sure that within 20 years we will create a computerized bacterium that will work exactly like its counterpart in the test tube in the laboratory and maybe even like its counterpart in the human body.

Preventing tuberculosis is, of course, better than treating someone who has already contracted it. To this end, efforts are being made to create a vaccine that will protect against the disease as well as the BCG component. Some developers try to improve the existing component, and others try to create completely new components. In the meantime, the work is conducted by trial and error because we do not understand why the current ingredient is ineffective, nor can we predict which ingredient will work without testing on humans.

Regarding other diseases for which vaccine components have been found - those who survive the initial infection are vaccinated against future infections. However, primary infection with tuberculosis does not provide such protection. Therefore a vaccine based only on a weakened tuberculosis bacterium will not protect against the disease. Unlike drug development, which seems to be greatly accelerated after the development of a computerized bacterium, the development of a successful vaccine component will require not only a computerized bacterium but also a computerized human. This way we can systematically examine how changes in the bacteria affect the human response.

In his book "The Turning Point" Malcolm Gladwell defines this point as "a stage where it is no longer possible to stop the impulse to change." There has never been a more urgent need for better diagnostic tests, drug treatments and vaccine components against tuberculosis. Much work is still ahead of us, but after the determination of the genomes of Homo sapiens and Mycobacterium tuberculosis, and with the help of the best minds dealing with the problem on an unprecedented scale, it is no longer possible to stop the change.

key concepts

Tuberculosis is second only to AIDS when it comes to causing death in the world due to infection, and the epidemic is spreading in many parts of the world.

Most patients with the disease, caused by bacteria, can be treated, but strains resistant to drugs from the first tier and even drugs from the second tier are multiplying and increasing.

Most conventional approaches to developing new antibiotic drugs and vaccine components have failed.

New tools allow scientists to study the bacterium that causes tuberculosis in great detail and provide unprecedented insights into the interrelationship between the disease agent and the host. The results reveal new and promising targets for drug therapy.

Schedule

Man against bacteria

Tuberculosis has been haunting humans for hundreds of thousands of years. Here are some important events in this prolonged battle between humans and the cause of the disease.

500,000 ago

Tuberculosis begins to infect man's ancestors.

1882

Robert Koch identifies the bacterium Mycobacterium tuberculosis, or Mtb, as the cause of tuberculosis.

1908

Albert Klemt and Kami Guern develop the BCG compound against tuberculosis. Then it turns out that the vaccine is consistently effective only against severe childhood strains.

1921

The beginning of the use of the BCG component.

1943

A team led by Zalman Waxman creates the first effective antibiotic drug against tuberculosis: streptomycin.

The 60 years

The treatment procedure used to this day is being developed: taking four types of medication for six to nine months.

The 70 years

Many assume that tuberculosis is almost eradicated.

1981

Scientists identify the AIDS virus, HIV, which causes excessive vulnerability to tuberculosis.

1998

The gene sequence of the tuberculosis bacterium was determined.

2005

The US Food and Drug Administration approves an improved test to diagnose tuberculosis.

2006

An outbreak of extensively drug-resistant tuberculosis, XDR-TB, in KwaZulu-Natal, South Africa.

Famous victims

Tuberculosis claimed the lives of many great luminaries, including: the three Brontë sisters, Anton Chekhov, Frederic Chopin, John Keats, King Louis XVIII of France, Moliere, George Orwell, Cardinal Richelieu, Jean- Jacques Rousseau, Erwin Schrödinger, Henry David Thoreau

Eye-opening facts

A third of the world's population is infected with the tuberculosis bacterium

1 out of every 10

will develop active tuberculosis in their lifetime

On average

4 out of every 10

Tuberculosis cases are not recognized and treated properly.

Tuberculosis is responsible for the death of people

every 20 seconds.

It is estimated that more are added every year

490,000

Tuberculosis patients who carry drug-resistant strains from the first tier and 40,000 tuberculosis patients who carry drug-resistant strains from the second tier.

Basic facts about infection

bad breath

Tuberculosis, caused by the bacterium Mtb, exists in a latent form and in an active form. People can also catch it if they breathe into their lungs a few individual TB bacteria released into the air by a patient with active TB after coughing, spitting or talking. The most common symptom caused by the bacteria is a cough due to the accumulation of an abundance of bacteria in the lungs. However, the bacteria may also damage other organs.

Tuberculosis bacteria tend to accumulate in the alveoli or in the alveoli because they prefer oxygen-rich environments. The immune systems of most people manage to limit the distribution of bacteria by sending defense cells, macrophages, to the infected sites. The macrophages form a shell around the bacteria. In 10% of those infected, the tuberculosis bacteria break through the shell and begin to multiply.

A scan showing a TB bacteria infection in the lungs.

After they are freed from the chains of the immune system, the bacteria destroy the lung tissue. Some may reach the bloodstream and infect other organs in the body, including the brain, kidneys and bones. Eventually the damage overwhelms the organs, they stop functioning and the patient dies.

the affected countries

Worldwide durability

Tuberculosis patients are actually found in all countries of the world, although it is mostly common in developing countries. The rate of tuberculosis caused by strains of bacteria that are resistant to two or more drugs of the first line of treatment for the disease, known as strains with multidrug resistance (MDR-TB), is increasing due to the incorrect use of antibiotic drugs. Even worse is extensively drug-resistant tuberculosis (XDR-TB), a strain identified in 2006 that is nearly impossible to treat. Until June 2008, 49 countries [including Israel - the editors] confirmed that this tuberculosis was diagnosed in them. Unfortunately, this is probably an underestimation of the prevalence of XDR-TB.

the way forward

Promising approaches to treatment

The first-line drugs used today to treat tuberculosis were developed in the 50s and 60s. The treatment regimen they prescribe lasts six to nine months. Failure to complete it resulted in the emergence of drug-resistant tuberculosis strains. There is therefore an essential need to develop materials that are easier and cheaper to supply and that will attack the tuberculosis bacteria in new ways.

Today: Traditional trial-and-error approaches to identifying anti-tuberculosis drugs have led to the discovery of several new candidates in clinical trials.

in the future:

Recently, scientists have been trying to get to know the tuberculosis bacterium in much more meticulous detail than before. They do this by studying the bacterium's genome and other cell components. This research yields new insights that explain how the bacterium establishes itself in the human body and what its weak points are. The researchers are supposed to inhibit ATP synthesis much more efficiently than the drugs currently in development. In addition, they will probably be able to find compounds that will stimulate the bacteria to release quantities of nitrogen monoxide, a compound that prevents cellular respiration, greater than the quantities released under the influence of substances found today. Blocking the synthesis of niacin, the main energy carrier in the bacterial cell, is another approach that has a reasonable chance.

In the distant future

Ultimately, the researchers want to create a computerized model of the tuberculosis bacterium that will behave exactly like its real counterpart in the human body. Such a model will allow them to predict the bacteria's reaction to different compounds with greater accuracy than is possible today.

About the authors

Clifton A. Barry III directs the Division of Tuberculosis Research at the Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIAID), which he joined in 1991. Berry's research group investigates all aspects of drug discovery against tuberculosis and the genomics of the bacterium and carries out a clinical trial program involving patients from South Korea who have a very resistant strain of tuberculosis. Maya S. Cheung is a research fellow at NIAID. She is a graduate of Middlebury College and plans to attend medical school in the fields of public health and infectious diseases.

in the battle trenches

The role of new drugs in the fight against TB is crucial, but public health officials cannot afford to wait until they reach the market. In the meantime, programs such as the "Stop TB" collaboration program of the World Health Organization are trying to curb the epidemic, in part by improving quality control in diagnostic facilities, increasing supervision of patients and supporting them, ensuring the supply of drugs and educating the public about issues related to treatment. The goal of the program is to reduce the number of deaths from tuberculosis by more than 50% by 2015.

And more on the subject

The Forgotten Plague: How the Battle against Tuberculosis Was Won – and Lost. Frank Ryan. Little, Brown, 1993.

magic mountain Thomas Mann, Hebrew translation Mordechai Avi Shaul, Hapoalim Library, 1955.

Building a Better Tuberculosis Vaccine. Douglas B. Young in Nature Medicine, Vol. 9, no. 5, pages 503–504; 2003.

Multidrug Resistant Tuberculosis in Russia. Merrill Goozner in ScientificAmerican.com; August 28, 2008. Available at www.SciAm.com
/report.cfm?id=tuberculosis-in-russia

PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release. Ramandeep Singh et al. in Science, Vol. 322, pages 1392–1395; November 28, 2008.

Why did the completion of decoding the tuberculosis virus make waves?