TB Background & Overview

M. tuberculosis, and to a lesser degree M. bovis and M. africanum, can cause a chronic and fatal condition in humans known as tuberculosis (TB).1 Until about 50 years ago, this disease was considered virtually incurable. The discovery of several active anti-TB agents, however, beginning with streptomycin in the early 1940s, heralded a new age of anti-TB chemotherapy; a cure for this dreaded disease that had plagued humanity since the dawn of civilization was now possible.2,3 Unfortunately, in only a few years, it became apparent that the use of these miracle drugs as single agents led to rapid drug resistance and treatment failures among a substantial number of patients.2,4 It was quickly realized, however, that the development of resistance could be forestalled or prevented through treatment with several active agents at once in a combination regimen.2,4 From this point in history, TB was considered a curable disease. In fact, until only recently, public health officials in the United States predicted that TB would be totally eradicated in this country by the year 2000.

Factors in the TB Resurgence

  • AIDS epidemic
  • Immigration from countries with TB epidemics
  • Increased poverty, injection drug use, homelessness
  • Viable treatments offer challenging dose regimens
  • Increased numbers of residents in long-term care facilities

By the late 1980s, however, TB reappeared as a serious threat to public health. In 1993, 25,287 cases of active TB were reported for all 50 states and the District of Columbia to the Centers for Disease Control (CDC), an increase of 14% since 1985.1,5 Although this number decreased to 22,860 by 1995, an estimated 15 million people in the United States may now have latent TB that could progress to active disease within their lifetime.1 In some segments of U.S. society, the TB rates surpass those in the world’s poorest nations.1,6 Several factors contributed to the reemergence of the disease in the U.S., including a steady decline in mandated public health standards concerning TB, increased numbers of patients in long-term care facilities, overcrowding in prisons, increased immigration from countries with a high incidence of TB, and large increases in the inner city homeless population.1,3,6 These factors have been overshadowed by the relatively recent epidemic of the human immunodeficiency virus (HIV), and the development of AIDS in a large population.7 TB commonly has a much earlier onset in AIDS patients than other opportunistic pathogens and is oftentimes hard to detect by standard techniques such as a positive tuberculin skin test that relies on a potent immune reaction not possible in the immunocompromised.8

Tuberculosis: The Problem

  • 1.7 billion infected worldwide
  • 8 million new cases per year
  • 3 million deaths per year
  • Multidrug resistant TB (MDR-TB) populations within the TB species now unaffected by traditional TB treatments

Worldwide, TB statistics are even more staggering. It is estimated that one third of the world’s population is infected with TB, with about 8 million new cases annually.9,10 Of these, 3.1 million die annually, more deaths than caused by malaria or any other single infectious disease.9,10 TB is the leading killer of youths, women, and AIDS patients in the world.9 It has been estimated that up to 50 million people are infected with drug-resistant forms of TB.2,9  The development of drug resistance in the population has increased concern that TB may once again become an incurable disease. Of particular concern is the development of multi-drug-resistant forms of the disease (MDR-TB), defined as forms resistant to two or more of the front line anti-TB agents 2,9,11-14 These forms of the disease are more often fatal and are difficult15 and expensive to treat. In industrialized nations, standard TB treatment costs on the order of $2,000 (US) per patient, but escalates more than 100-fold in patients with MDR-TB, to as much as $250,000.9 Such costs are difficult to bear in industrialized nations, and even less so in developing countries. These problems are further exacerbated by the lack of political commitment worldwide to establish long-term and effective tuberculosis treatment and control programs.16

Anti-TB Drug Discovery

History

In 1943, anti-TB research resulted in discovery of the active anti-TB agent streptomycin.2 A number of agents have been discovered since that time, including para-aminosalicylic acid (1946), INH (1952), pyrazinamide (1952), cycloserine (1952), ethionamide (1956), RMP (1957), and ethambutol (1962).2 The majority of these drugs were discovered through broad screening; very little optimization was undertaken and little regard was given to the targets of drug action since the biochemical tools for these studies were not as sophisticated as they are now. This lack of understanding of drug action was compounded by a profound ignorance of the biochemistry of the M. tuberculosis bacillus. In fact, among other reasons, the difficulty in manipulating M. tuberculosis has hindered efforts to delineate the mode of action of these agents. Recent improvements in biological techniques have allowed the mechanisms of action of many of these agents to be uncovered and more carefully studied.17 Current treatments involve multiple drug regimens that extend for months at a time, and the pharmacology of these treatment regimens can be complex,18-20 especially for the treatment of multiple drug-resistant forms of TB.13

Future Directions

There are many new approaches for discovering new, more selective anti-TB agents:21-23 the mapping of the M. tuberculosis genome;24-27 the delineation of many of the pathways in mycobacterial cell wall biosynthesis (e.g., glycosylation pathways, fatty acid biosynthesis, and diaminopimelic acid biosynthesis);28-33 the discovery of genes involved in latency and virulence;31-34 and the application of DNA microarray technology to M. tuberculosis. Furthermore, the application of combinatorial chemistry and high-throughput screening to anti-TB drug discovery promises to greatly accelerate the drug discovery process.

NIAID and Tuberculosis

The rapid development of new and improved therapies has been hampered by a relatively low level of interest on the part of the private sector, principally due to the perception of limited markets. In its mission to stimulate research towards discovery of improved therapies, NIAID, the lead institute for TB research at the NIH, has formulated a comprehensive research agenda to address this growing problem in the U.S.1 This renewed emphasis should impact treatment worldwide. Increased support is being made available for: (1) studies of the epidemiology and natural history of TB; (2) basic research into the biology of TB; (3) the development of new tools to diagnose TB; (4) clinical trials of anti-TB therapies; (5) the development of new vaccines to prevent TB; (6) training to increase the number of TB researchers; (7) new ways to educate health care workers and the public about TB prevention; and (8) the development of new drugs or ways to deliver standard drugs.1 New drugs and improved delivery methods will be integral parts of a strategy to fully control future outbreaks of TB, particularly MDR-TB, which has severely challenged the limited number of effective treatment options.1

Reference List

  1. NIAID, Web Site, http://www.niaid.nih.gov/ for a review of tuberculosis and the NIAID mission to address the disease.
  2. WHO (1997). Anti-tuberculosis Drug Resistance in the World: The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1994-1997, WHO/TB/97.229.
  3. Daniel, T.M.; Bates, J.H.; Downes, K.A. History of Tuberculosis. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 13-24.
  4. Snider, D.E. and Castro, K.G. The Global Threat of Drug-Resistant Tuberculosis. New. Engl. J. Med., 1998, 338, 1689-90.
  5. For a review of tuberculosis trends in the United States see Tuberculosis Morbidity-United States, 1997. MMWR, 1998, 47, 1-5 and Moore, M.; Onorato, I.M.; McCray, E.; Castro, K.G. Trends in Drug-Resistant Tuberculosis in the United States, 1993-1996. JAMA, 1997, 278, 833-7.
  6. Friedman, L.N.; Williams, M.T.; Tejinder, B.A.; Singh, P.; Frieden, T.R. Tuberculosis, AIDS, and Death Among Substance Abusers in New York City. , New. Engl. J. Med., 1996, 334, 828-833.
  7. Murray, J.F. Tuberculosis and HIV Infection: A Global Perspective. 1998, 65, 335-342.
  8. Hopewell, P.C. Overview of Clinical Tuberculosis. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 25-46.
  9. WHO, Web Site, http://www.who.int/ and links for an overview of tuberculosis worldwide.
  10. Snider, D.E. Jr.; Raviglione, M.; Kochi, A. Global Burden of Tuberculosis, Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 3-11.
  11. Basso, L.A.; Blanchard, J.S. Resistance to Antitubercular Drugs. Adv. Exp. Med. Biol. 1998, 456, 115-144.
  12. Bradford, W.Z.; Daley, C.L. Multiple Drug-Resistant Tuberculosis. Infectious Dis. Clin. North Am. 1998, 12, 157-172.
  13. Bastian, I.; Colebunders, R. Treatment and Prevention of Multidrug-Resistant Tuberculosis. Drugs, 1999, 58, 633-66.
  14. Cohn, D.L.; Bustreo, F.; Raviglione, M.C. Drug-Resistant Tuberculosis: Review of the Worldwide Situation and the WHO/IUATLD Global Surveillance Project, Clinical Infectious Disease, 1997, 24, S121-130.
  15. Sung, S.-W.; Kang, C.H.; Kim, Y.T.; Han, S.K.; Shim, Y.-S.; Kim, J.H. Surgery increased the chance of cure in multi-drug resistant pulmonary tuberculosis. European Journal of Cardio-thoracic Surgery, 1999, 16, 187-193.
  16. Efferen, L.S. Tuberculsosi Update: Will Good News Become Bad News? Current Opinion in Pulmonary Medicine, 1997, 3, 131-138.
  17. Rattan, A.; Kalia, A.; Ahmad, N. Multidrug-Resistant Mycobacterium Tuberculosis: Molecular Perspectives. Emerging Infectious Diseases, 1998, 3, 195-209.
  18. Gray, M.A. Tuberculosis Drugs. Orthopaedic Nursing, 1997, 16, 64-67.
  19. Bishai, W.R.; Chaisson, R.E. Short-Course Chemoprophylaxis for Tuberculosis. Clinics in chest Medicine, 1997, 18, 115-122.
  20. Douglas, J.G.; McLeod, M.-J. Pharmacokinetic Factors in the Modern Drug Treatment of Tuberculosis. 1999, 37, 127-146.
  21. Schraufnagel, D.E. Tuberculosis treatment for the beginning of the next century. Int. J. Tuberc. Lung Dis., 1999, 3, 651-662.
  22. Yew, W.W.; Chau, C.H. Future Directions in the Development of New Antituberculosis Drugs. Drugs and Aging, 1997, 10, 405-410,
  23. Mitscher, L.A.; Baker, W. Tuberculosis: A Search for Novel Therapy Starting with Natural Products. Med. Res. Rev., 1998, 18, 363-374.
  24. Duncan, K. The impact of genomics on the search for novel tuberculosis drugs. Novartis Foundation Symposium, 1998, 217, 228-238.
  25. Cole, S.T. and Smith, D.R. Toward Mapping and Sequencing the Genome of Mycobacterium Tuberculosis. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 227-238.
  26. Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.V.; Eiglmeier, K.; Gas, S.; Barry III, C.E.; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell. T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.;Quail, M.A.; Rajandream, M.-A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J.E.; Taylor, K.; Whitehead, S.; Barrell, B.G. Deciphering the Biology of Mycobacterium Tuberculosis from the Complete Genome Sequence. Nature, 1998, 393, 537-544.
  27. Young, D.B. Blueprint for the White Plague. Nature, 1998, 393, 515-516.
  28. Kolattukudy, P.E.; Fernandes, N.D.; Azad, A.K.; Fitzmaurice, A.M.; Sirakova, T.D. Biochemistry and Molecular Genetics of Cell-Wall Lipid Biosynthesis in Mycobacteria, Molecular Microbiology, 1997, 24, 263-270.
  29. Besra, G.S. and Chatterjee, D. Lipids and Carbohydrates of Mycobacterium Tuberculosis. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 285-306.
  30. Young, D.B. Strategies for New Drug Development. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 559-567.
  31. Barry III, C.E. New Horizons in the Treatment of Tuberculosis. Biochemical Pharmacology, 1997, 54, 1165-1172.
  32. McNeil, M. Targeted Preclinical Drug Development for Mycobacterium Avium Complex: A Biochemical Approach in Mycobacterium Avium Complex Infection, Koravick and Benson editors; Marcel Dekker Publishers, New York, NY: 1996, Chapter 10, pp 263-283.
  33. Brennan, P.J.; Nikaido, H. The Envelope of Mycobacteria. Annual Reviews in Biochemistry, 1995, 64, 29-61.
  34. Jacobs, W.R. Jr.; Bloom, B.R. Molecular Genetic Strategies for Identifying Virulence Determinants of Mycobacterium Tuberculosis. Tuberculosis: Pathogenesis, Protection, and Control, Barry Bloom editor; ASM Press, Washington, D.C.: 1994, pp 253-268