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by Karen J. Kieser
figures by Karen J. Kieser

Tuberculosis (TB) has been a disease of humankind for millennia, and rising rates of drug resistance threaten humanity’s ability to arrest its spread. Compared to common bacterial infections, such as strep throat, which can often be treated with one pill a day for ten days, TB treatment is an immense burden (Figure 1). Drug-sensitive TB demands 6-9 months of multiple pills a day. Drug-resistant TB is even worse, requiring 18-24 months of treatment – including daily injections and multiple pills. Even with this voluminous drug cocktail, the chance of becoming disease-free is just fifty percent for patients with drug-resistant TB. To address this problem, new clinical trials are testing the first anti-TB drugs developed in almost half a century and aim to reduce drug-resistant TB treatment to 6-9 months and just pills.

Tuberculosis still consumes lives

Consumption, as TB was widely known in the 19th century, remains a prevalent threat today. Data from the World Health Organization (WHO) has shown that TB surpasses HIV in the number of individuals it kills each year. TB took an estimated 1.4 million lives in 2015 (HIV killed 1.1 million that same year, according to the WHO). Additionally, latent TB infections, in which individuals harbor bacteria that are not growing and thus exhibit no symptoms, are estimated to make up one third of the global population. However, latent bacteria can re-grow, causing disease, and thus comprise a large pool of disease risk. Compounding the problem are the escalating rates of drug resistance in Mycobacterium tuberculosis, the bacterium that causes TB. In fact, the WHO estimates over half a million people were diagnosed with drug-resistant TB in 2015, among 10.4 million new cases that year alone.

Figure 1. Cocktails, anyone? Typical treatment for common bacterial infections, such as strep throat, usually consists of 1 pill daily for 10 days. Drug sensitive TB requires 4 separate drugs dosed daily for 8 weeks and then 2 drugs dosed daily for at least 16 weeks, sometimes longer. Drug resistant TB requires even more antibiotics, with a typical program requiring patients to take 5 drugs a day (with at least one being injectable) for 32 weeks and then a continuation phase for an additional 40 weeks, but which can extend to 56 weeks if needed. There is no universal regimen, as drug-resistant treatment programs are tailored to the patient’s disease and level of resistance.
Figure 1: Cocktails, anyone? Typical treatment for common bacterial infections, such as strep throat, usually consists of 1 pill daily for 10 days. Drug sensitive TB requires 4 separate drugs dosed daily for 8 weeks and then 2 drugs dosed daily for at least 16 weeks, sometimes longer. Drug resistant TB requires even more antibiotics, with a typical program requiring patients to take 5 drugs a day (with at least one being injectable) for 32 weeks and then a continuation phase for an additional 40 weeks, but which can extend to 56 weeks if needed. There is no universal regimen, as drug-resistant treatment programs are tailored to the patient’s disease and level of resistance.

Bacteria versus antibacterials

Treating TB is difficult and requires a cocktail of antibiotics. TB patients take what is known as combination therapy, consisting of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) for two months. Combination therapy is needed because the TB bacterium is difficult to kill, and it helps reduce the emergence of drug resistance (evolving resistance to multiple drugs simultaneously is much harder than evolving resistance to a single drug). Treatment is then reduced to isoniazid and rifampicin, which must be taken for an additional four to seven months. These antibiotics form what is called “first-line” therapy and come packed with poor side effects, including nausea, skin rashes, and joint pain.

Isoniazid and rifampicin are the two most powerful drugs against TB, and resistance to these two drugs marks TB bacteria as multi-drug resistant (MDR), one of several forms of drug resistance in TB. A more pernicious variety is extensively drug-resistant TB (XDR-TB). XDR-TB bacteria are resistant to isoniazid and rifampicin, as well as two additional, and distinct, classes of “second-line” drugs, so classified because they are less effective and more toxic than first-line anti-TB drugs. Common side effects of these second-line antibiotics include heart rhythm irregularities, skin discoloration, and neuropathy.

The first new anti-TB drugs in almost 5 decades

These first- and second-line therapies leave much to be desired, and new drugs could dramatically improve patient lives and outcomes. Indeed, two new clinical trials, TB-PRACTECAL and endTB, are testing the first antibiotics to be developed against TB in almost fifty years: bedaquiline and the two related drugs pretomanid and delamanid. The trials are run by major global health organizations, including Médicins sans Frontières, Partners in Health, the WHO, and other groups. TB-PRACTECAL, which tests bedaquiline and pretomanid, began in mid-January in Uzbekistan. endTB, which examines bedaquiline and delamanid, rolled out in the nation of Georgia in March. Both trials will use the new drugs in combination with several current second-line therapies. The clinical trials are multi-national, with patients in South America, Eastern Europe, Southeast Asia, and southern and eastern Africa. These trials focus specifically on drug-resistant TB because the drugs still exhibit some safety concerns, making their widespread use in all TB patients not yet practical.

Two of the new drugs have a “classic” method of killing bacteria. Many antibiotics, such as penicillin, kill bacteria by blocking the function of proteins that make the bacterial cell wall. Without strong cell walls, bacteria fall apart and die. These types of proteins are attractive drug targets because they do not exist in mammals, reducing the chance that the drug will kill human cells during treatment. Pretomanid, and its structural and more potent cousin delamanid, inhibit the activity of an as yet unknown protein and block construction of the TB cell wall (Figure 2A). However, delamanid can lead to heart rhythm irregularities.

Figure 2. New drugs take out TB. A) Pretomanid and delamanid kill cells in a “classic” method by inhibiting synthesis of the bacterial cell wall. These drugs block the activity of an as yet unknown protein involved in making the cell wall. Blocking its function causes abnormalities in cell wall assembly, and the bacterium dies. B) Bedaquiline kills bacteria by binding to a subunit of the energy-generating machine of the cell, known as ATP synthase. This blocks the ability of ATP synthase to generate energy, and without energy, bacteria fail to execute basic cellular functions and die.
Figure 2: New drugs take out TB. A) Pretomanid and delamanid kill cells in a “classic” method by inhibiting synthesis of the bacterial cell wall. These drugs block the activity of an as yet unknown protein involved in making the cell wall. Blocking its function causes abnormalities in cell wall assembly, and the bacterium dies. B) Bedaquiline kills bacteria by binding to a subunit of the energy-generating machine of the cell, known as ATP synthase. This blocks the ability of ATP synthase to generate energy, and without energy, bacteria fail to execute basic cellular functions and die.

The discovery of the other new drug, bedaquiline, opened up a new class of drugs for TB. Bedaquiline kills TB bacteria by jamming the protein machine that produces ATP – the energy currency of the cell (Figure 2B). Without energy production, it is impossible for a cell to survive. While both human and microbial cells have similar ATP synthases (the ATP-producing protein machine), bedaquiline is specific for the bacterial version, due to two amino acid differences in the pocket into which bedaquiline fits. However, there are still safety concerns with bedaquiline, including an unexplained increased patient rate of mortality as well as irregular heart rhythms.

Nevertheless, there is now hope – and scientific evidence – that these new antibiotics will be effective against drug-resistant TB. The very first late-stage clinical trial to test two of these new drugs, called Nix-TB, began in 2015 and is still ongoing. Nix-TB examines bedaquiline, pretomanid, and another second-line drug in patients with XDR-TB or difficult to treat MDR-TB. The team recently publicized interim results: of 34 individuals who completed 6 months of treatment, all patients were TB bacteria free at 4 months. These are remarkable, and unexpected, results. TB-PRACTECAL and endTB will provide further data on the new drugs and expand our understanding of their effectiveness in geographically distinct populations.

Strength in diversity: new TB drugs are still needed

The import of bedaquiline and delamanid was underscored when, in 2015, the WHO listed them as essential medicines, drugs that are fundamentally needed to ensure a functional health system. Both drugs still exhibit safety issues, however, and new drug development for TB is critical. Despite being a global health crisis, the WHO recently declined to include TB on its “global priority pathogens list” of drug-resistant bacteria that need new drugs. In an editorial, it was argued this was because the WHO has campaigned for TB drug development in separate programs. Arguably, as the world’s top bacterial killer and with rising antibiotic resistance, TB drug development needs all the advocacy it can get. In the past few years, major pharmaceutical companies have pulled out of TB drug development, including Novartis, Pfizer, and AstraZeneca. Without a stacked deck, the chance of developing potent, and safe, drugs against antibiotic-resistant TB grows dimmer. Other organizations are filling the gap, including corporations and academic groups. The promising results of the Nix-TB trial demonstrate that drug development for TB – even drug-resistant TB – can yield impressive new antibiotics. Hope for TB patients lies in continued persistence and creativity, spheres where scientists and public health practitioners excel.

Karen J. Kieser completed her PhD in the Biological Sciences in Public Health Program at Harvard University where she studied cell wall synthesis in Mycobacterium tuberculosis. Karen is currently a postdoctoral researcher at Harvard Medical School/Boston Children’s Hospital.

For more information:

Paul Farmer, co-founder of PIH, on TB and the endTB trial in the New York Times
A Guardian piece on rising drug-resistant tuberculosis
Science news piece on the results of the Nix-TB trial
Open access Nature Reviews Disease Primers on tuberculosis
The recently minted Public Library of Science channel on tuberculosis
Nature Microbiology Community blog collection on TB research and policy
Médicins sans Frontières blog with MDR-TB patient stories about their treatment

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