Why Is Tuberculosis Still a Problem?

by | CRO, Pharmaceutical

Publish Date: March 24, 2023

The bacterial pathogen Mycobacterium tuberculosis (Mtb) has plagued humans for probably 70,000 years and remains a global threat to this day.1, 2 In 1882, Robert Koch recognized Mtb as the causative agent of tuberculosis (TB), but it took decades for the first effective anti-TB antibiotics to be developed in 1944.2 Mycobacterium tuberculosis is still responsible for more deaths worldwide than any other infectious agent, with new cases exceeding 10 million per year and annual deaths consistently passing 1 million. Tuberculosis is believed to have been the cause of over one billion deaths in the last 200 years.1 The biggest challenges for eradicating, treating, or eliminating TB are drug-resistant TB and co-infection with human immunodeficiency virus (HIV).1, 2 Like many difficult-to-eradicate bacterial pathogens, TB needs to infect, survive, and replicate within human cells; its ability to do so allows it to evade the host immune system that would typically act to control it. With World TB Day approaching on March 24th, it is timely to refresh our understanding of this lethal organism and how it skirts the dangers presented by host defenses.

TB Infection

Mycobacterium species cause a variety of illnesses, including Hansen’s disease, or leprosy, as it is commonly called, which results from Mycobacterium leprae.4 The species M. africanum, which is endemic to the continent of Africa, causes TB-like symptoms.5 M. bovis often produces TB symptoms in cattle, though humans may also become infected, often through raw milk from infected cattle.6

Typically, TB is spread via aerosolized particles; once inhaled, the bacillus can become trapped in the upper airways and then gain access to the lower respiratory tract. The bacteria usually remain in the lungs but in some cases can spread to other organs.3 An estimated 25% of the global population is infected with tuberculosis, though most people display no symptoms, as their immune systems keep the infection in check. When an individual presents no symptoms, this is called latent TB infection (LTBI).5 In some cases, people with LTBI may never develop active TB, but for others, the infection can emerge and cause and TB disease.5 The risk of developing active TB is much higher in people with weaker immune systems and/or those with HIV infection.5

Symptoms of tuberculosis lung infection include:

  • A severe cough lasting three weeks or more
  • Chest pain
  • Coughing up blood or sputum
  • Fatigue or weakness
  • Weight loss
  • Lack of appetite
  • Chills, fever
  • Sweating at night

The infection cycle of TB is shown graphically in Figure 1. The figure shows a hallmark of TB infection, a “granuloma”; this is a structured cluster of cells with M. tuberculosis-infected macrophages at the center, surrounded by other immune system cells.6 The M. tuberculosis infection stimulates the formation of these granulomas. Within these granulomas, the bacteria can persist for years, even through the lifetime of the host.9 There is some evidence that as the bacteria replicate within macrophages, they cause the death of their host cells, and as new macrophages swarm in to “clean up” those dead cells, they then become infected themselves.9 This process enables the bacteria to quickly expand their numbers. In this way, M. tuberculosis is able to flip the host response to invading bacteria to its own advantage.

Tuberculosis infection

Figure 1 Tuberculosis infection in humans
Tuberculosis is transmitted when aerosol particles containing the bacteria are dispersed via coughing and inhaled into the lower lungs of a new host. Macrophages are recruited to the interior lung surface by the bacilli and become infected; in some cases, these infected macrophages can cross the lung epithelia to deeper tissues. Granulomas can form when more macrophages and other immune cells arrive to the infection site; some of these cells are infected and become necrotic. This necrotic center of the granuloma supports bacterial growth and further transmission to a new host.9

It is believed that the granulomas present during active disease can have a wide range of structures, with bacteria-laden lesions as well as large open cavities, whereas during a latent TB infection, closed granulomas with central necrotic lesions containing few bacteria are observed.10

TB Intracellular Survival

Unlike many bacterial pathogens, Mtb does not rely on virulence factors or toxin production to infect its hosts, but has developed a strategy to evade, modulate, and exploit the host immune system to act in its favor.9 A specific lipid on the bacterial surface is key to directing Mtb to host phagocytic cells, namely macrophages or other immune cells. Normally, invading bacteria are phagocytosed and killed by macrophages and neutrophils in the lungs, but TB Mtb has evolved a strategy of preventing the main mechanism of bacterial eradication, that of fusion of the phagosome with lysosomes. Lysosomes are cellular organelles that are filled with enzymes that can degrade invaders such as bacteria (Figure 2). Safely inside phagosomes, Mycobacteria can replicate to large numbers or escape into the main cellular compartment of the cytosol where they can multiply until the cell bursts, and the bacteria can go on to infect fresh cells.9

Tuberculosis Infection

Figure 2 Graphic of Mycobacterium tuberculosis strategy of intracellular survival
Mycobacteria tuberculosis has evolved a strategy for intracellular survival following engulfment by immune cells (left side of graphic) compared to normal degradation that occurs when these cells engulf invading bacteria (right side of graphic). Source: Adapted from 9, Figure 1.


Drug-resistant M. tuberculosis is a huge challenge since, as discussed below, treatment for this infection involves regimens of several anti-TB agents. Drug-resistant TB Mtb is defined as those bacteria that are resistant to at least one first-line anti-TB drug, whereas multidrug-resistant TB Mtb (MDR-TB) are those that are resistant to more than one anti-TB drug, including at least isoniazid (INH) and rifampin (RIF). Most troubling are cases of extensively drug-resistant TB Mtb (XDR-TB) – these are resistant to INH, RIF, plus a fluoroquinolone-class drug as well as at least one of three second-line drugs (such as kanamycin, amikacin, or capreomycin).12 Drug-resistant TB Mtb can arise when drugs used to treat this infection are misused, or the full course of therapy is not completed, or the incorrect drugs are given.12

The nearly 10.4 million cases of TB in 2017 included some 558,000 cases that were rifampicin-resistant TB (RR-TB) and of these, 82% were multidrug-resistant TB. Of the multi-resistant infections, 8.5% were XDR-TB.13 The global distribution of RR-TB and MDR-TB cases in 2017 is shown in Figure 3.

Tuberculosis resistance rates
Figure 3 Global distribution of TB drug resistance for rifampicin-resistant/multidrug-resistant (RR/MDR-TB) and extensively drug-resistant (XDR-TB), 2017. Source: 11, Figure 1

Treatment Challenges

Even though anti-TB drugs were discovered in the late 1940s (streptomycin, isoniazid, and para-aminosalicylic),13 morbidity and mortality caused by tuberculosis remains high—treatment of this infection is complicated by several factors: the intracellular nature of this organism requires that anti-TB drugs penetrate cells and cellular compartments to access the bacteria; the slow growth of this organism makes finding the source of infection difficult, delaying treatment (and therefore compliance is a challenge); resistance, in particular multi-drug resistance, requiring the administration of multiple antibiotics with adverse side effects; the dormant state of this organism, especially in latency; and, in developing countries, the high incidence of HIV co-infection.4, 11 The latter lowers the host immune response and allows TB to flourish.3, 13

Treatment of drug-susceptible pulmonary TB can vary in the duration, in the types of anti-TB drugs, and in the dose and frequency of administration. Typically, two regimens are recommended by the CDC for treating drug-susceptible pulmonary TB:

  • 4-month regimen of high-dose rifapentine-moxifloxacin-isoniazid-pyrazinamide (RPT-MOX-INH-PZA) consisting of 2 months of high-dose therapy, followed by a continuation phase of 2 months plus one week, for a total of 17 weeks of treatment.
  • 6-to-9-month regimen of rifampin-isoniazid-pyrazinamide-ethambutol (RIF-INH-PZA-EMB) consisting of 2 months of high-dose therapy followed by a 4- or 7-month continuation phase, for a total of 6 to 9 months of treatment.12

Similar regimens are recommended for patients with latent TB infection or with HIV, as these present further challenges for clinicians.12

Options are more limited for patients who have drug-resistant TB but there is some indication that the recommended regimens have been having some success. Figure 4 shows the success rates for patients treated for TB based on data from the World Health Organization (WHO).3 Patients treated for infections due to TB had an 86% success rate in 2020, even during the COVID-19 pandemic, similar to the levels seen in 2019 (blue line in Figure 4). Patients co-infected with HIV had lower rates of treatment success in 2020 (77%), but these rates have been steadily improving.3 As shown in the figure in red, treatment for RR/MDR-TB has shown consistent progress over the last seven years, from a 50% success rate in 2012 to 60% in 2019. Newer drugs are being used (i.e., bedaquiline) to treat these infections, as well as strategies such as Directly Observed Treatment (DOTs), whereby healthcare workers observe patients as they ingest their doses to ensure compliance.3

TB Treatment Success Rates

Figure 4 Global success rates for patients treated for TB, 2012 to 2020. Source: (3) WHO Report, 2022, Figure 23.

TB Today

Tuberculosis continues to be a worldwide problem and had been even before WHO declared TB a global public health emergency decades ago. In 2019, TB was the 13th leading cause of death worldwide and the primary cause of death from a single infectious agent.3

An End TB Strategy was established by the World Health Organization and the United Nations (UN) in 2014 and 2015 as part of the UNs Sustainable Development Goals (SDGs). Targets were established for reducing the TB incidence rates and mortality by up to 5% per year by 2020 and by 10% per year by 2025, and then by an average of 17% per year from 2025 to 2035 (3) (Figure 6).3


Figure 5 Global trends in the estimated number of TB deaths (left) and mortality rate (right), 2000 – 2021
The horizontal dashed line indicates the 2020 milestone of the End TB Strategy, a 35% reduction in the total number of TB deaths from 2015 to 2020. Shaded areas represent uncertainty intervals of 95%. (Source: 3, Figure 5).

Funding for TB prevention, diagnostic, and treatment funding and vaccines were included as part of the global strategy.3 The incidence of reported TB in the United States decreased steadily during 1993 to 2019, then 2020 saw a substantial decline in cases.16 This was likely due to the mitigation efforts and travel restrictions imposed during the COVID-19 pandemic.16 TB cases in the United States increased by 9.4% during 2021 compared with 2020, perhaps due to delayed diagnoses of cases or to the lifting of COVID restrictions.16 The hope is that with continued efforts, the strategies put in place to reduce TB infections worldwide will have a substantial impact on global health.

Mycobacterium tuberculosis (MTBMtb) anti-infective screening services from Microbiologics

At our BSL3 facility in St. Cloud, we have validated broth microdilution susceptibility testing of MTB Mtb using custom frozen panels. These panels can be made to suit your screening needs with any number of investigational compounds alongside relevant comparators. We have a variety of MTB Mtb strains available for primary profiling, including susceptible isolates and reference isolates characterized for resistance to first line therapeutics along with MDR-TB and pre-XDR TB. Testing is conducted in accordance with CLSI guideline M24. Please contact your Microbiologics business development manager to arrange a meeting with our scientific team to discuss how we can support your anti-TB agent development needs.

Learn more.



  1. Bussi, G, and Gutierrez, MG, 2019. FEMS Microbiol Rev Vol 43, No 4.
  2. Loddenkemper, R., Murray, J.F. (2021). History of Tuberculosis. In: Migliori, G.B., Raviglione, M.C. (eds) Essential Tuberculosis. Springer, Cham. https://doi.org/10.1007/978-3-030-66703-0_1
  3. Global Tuberculosis Report 2022. WHO. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022.
  4. Hansen’s Disease (Leprosy). CDC. https://www.cdc.gov/leprosy/index.html.
  5. Gengenbacher, M and Kaufmann, SHE, 2012. Mycobacterium tuberculosis: Success through dormancy. FEMS Microbiol Rev 36: 514 – 532.
  6. Bovine TB in Humans Fact Sheet. CDC. https://www.cdc.gov/tb/publications/factsheets/general/mbovis.htm.
  7. Basic TB Facts | TB | CDC. https://www.cdc.gov/tb/topic/basics/default.htm.
  8. Pieters, J 2008. Mycobacterium tuberculosis and the macrophage: Maintaining a balance. Cell Host and Microbe. 3: 399 – 407.
  9. Cambier, CJ, Falkow, S, and Ramakrishnan, L. 2014. Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell 159: 1497 – 1509.
  10. Connolly, LE, Edelstein, PH, Ramakrishnan, L. 2007. Why is long-term therapy required to cure tuberculosis? PLOS Medicine 4(3):435 – 441.
  11. Warner, DF. and Mizhrahi, V. 2007. The survival kit of Mycobacterium tuberculosis. Nature Med.13(3): 282 – 284.
  12. Drug-Resistant TB. CDC. https://www.cdc.gov/tb/topic/drtb/default.htm.
  13. Mabhula, A and Singh, V. 2019. Drug-resistance in Mycobacterium tuberculosis: Where we stand. Med Chem Comm. 10: 1342 – 1360.
  14. Treatment for TB Disease. CDC. https://www.cdc.gov/tb/topic/treatment/tbdisease.htm
  15. Reported Tuberculosis in the United States, 2021. CDC. https://www.cdc.gov/tb/statistics/reports/2021/table1.htm
  16. MMWR/ March 25, 2022 / 71(12); 441–446

Written by Andrea Marra

Andrea Marra received a B.S. in Biology from the Massachusetts Institute of Technology and a Ph.D. in Microbiology from Columbia University, studying the genetics of Legionella pneumophila in Dr. Howard Shuman’s laboratory. Following two postdoctoral fellowships she developed her career working as the microbiology/pharmacology lead in Anti-infectives groups in big pharma and biotech companies (SmithKline Beecham, Protein Design Labs, Pfizer, and Rib-X/Melinta Therapeutics), gaining experience in ADME and toxicology as well. She eventually changed course to join Micromyx (now Microbiologics), where she currently works with clients to provide laboratory and consulting services for antimicrobial discovery and development, in addition to document preparation and report writing for teams across the organization. When not working, Andrea enjoys playing with her rescue dog, Newman, baking, and yoga.

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