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NUEVAS ESTRATEGIAS PARA LA INVESTIGACION Y DESARROLLO DE DROGAS ANTITUBERCULOSAS

(especial para SIIC © Derechos reservados)
El resurgimiento global de la TBC y la rápida emergencia de la variedad resistente a múltiples drogas y su asociación con el HIV subrayan la importancia de la creación de drogas antituberculosas nuevas más efectivas, sin resistencia cruzada y de bajo costo.
tomioka9.jpg Autor:
Haruaki Tomioka
Columnista Experto de SIIC

Institución:
Department of Microbiology and Immunology Shimane University School of Medicine

Artículos publicados por Haruaki Tomioka
Recepción del artículo
27 de Abril, 2005 		Aprobación
10 de Mayo, 2005
Primera edición
2 de Febrero, 2006 		Segunda edición, ampliada y corregida
7 de Junio, 2021

NUEVAS ESTRATEGIAS PARA LA INVESTIGACION Y DESARROLLO DE DROGAS ANTITUBERCULOSAS

Resumen
Debido a que la tuberculosis constituye un problema sanitario mundial, al aumento del tipo resistente a múltiples drogas y a la elevada tasa de coinfección con el HIV, urge la necesidad de crear nuevas y más potentes drogas antituberculosas sin resistencia cruzada con los antimicobacterianos conocidos. En este artículo se tratan los siguientes tópicos. En primer lugar, se discute la obtención de los nuevos fármacos antituberculosos en función de los blancos farmacológicos potenciales. A través de la información estratégica proveniente del estudio del genoma completo de Mycobacterium tuberculosis, en un futuro cercano se hará posible la creación de un fármaco que relacione cuantitativamente su estructura y actividad. En segundo lugar, se debate la utilidad de las nuevas tecnologías relacionadas con los liposomas y las microesferas, que permiten una provisión adecuada del fármaco a su sitio de acción en los pacientes tuberculosos. Tercero, describo la inmunoterapia complementaria para el tratamiento de la tuberculosis, a través de la administración de inmunomoduladores como las citoquinas potenciadoras del sistema inmune (IFN-γ, IL-2, etc.), los inhibidores del FNT-α, ATP y Mycobacterium vaccae inactivado por calor en combinación con fármacos tuberculostáticos. La inmunoterapia es promisoria para el desarrollo de nuevos tipos de regímenes antituberculosos asociados a quimioterapias antimicrobianas.

Palabras clave
Drogas antituberculosas, tuberculosis, Mycobacterium tuberculosis, blancos farmacológicos, biodisponibilidad del fármaco, inmunoterapia


Artículo completo
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NEW STRATEGIES FOR DEVELOPMENT OF ANTITUBERCULOUS DRUGS

Abstract
Because of the global health problems of tuberculosis (TB), the increasing rate of multidrug-resistant TB and the high rate of a co-infection with HIV, the development of potent new antituberculous drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, the future development of new antitubercular drugs is discussed according to the potential pharmacological targets. Using new critical information on the whole genome of Mycobacterium tuberculosis, drug development using quantitative structure-activity relationship may be possible in the near future. Second, the usefulness of liposome and microsphere technologies that enable efficacious drug delivery to their target in TB patients is discussed. Third, I describe adjunctive immunotherapy for the management of TB patients by giving certain immunomodulators, such as immunopotentiating cytokines (IFN-γ, IL-2 etc.), TNF-α inhibitors, ATP, and heat-killed Mycobacterium vaccae, in combination with antituberculous drugs. Immunotherapy using these adjunctive agents is promising for development of new types of anti-TB regimens in combination with antimicrobial chemotherapy.

Key words
Antituberculous drugs, tuberculosis, Mycobacterium tuberculosis, drug targets, bioinformatics, drug delivery, immunotherapy


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Especialidades
Principal: Farmacología, Infectología
Relacionadas: Bioquímica, Inmunología, Medicina Farmacéutica, Medicina Interna, Neumonología



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Bibliografía del artículo
  1. Tiruviluamala P, Reichman LB. Tuberculosis. Annu Rev Public Health 2002; 23:403-426.
  2. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003; 362:887-899.
  3. Iseman MD. Treatment and implications of multidrug-resistant tuberculosis for the 21st century. Chemotherapy. 1999; 45 (Suppl 2):34-40.
  4. Schraufnagel DE. Tuberculosis treatment for the beginning of the next century. Int J Tuberc Lung Dis 1999; 3:651-662.
  5. Tomioka H. Prospects for development of new antimycobacterial drugs. J Infect Chemother 2000; 6:8-20.
  6. Tomioka H. Type II pneumocytes in the evaluation of drug antimycobacterial activity. Expert Opin Pharmacother 2003; 4:127-139.
  7. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998; 393:537-544.
  8. Fleischmann RD, Alland D, Eisen JA, et al. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 2002; 184:5479-5490.
  9. Glickman MS, Jacobs WR. Microbial pathogenesis of Mycobacterium tuberculosis: Dawn of a discipline. Cell 2001; 104:477-485.
  10. Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 2003; 16:463-496.
  11. Duncan K. Identification and validation of novel drug targets in tuberculosis. Curr Pharm Design 2004; 10:3185-3194.
  12. Kantardjieff K, Rupp B. Structural bioinformatic approaches to the discovery of new antimycobacterial drugs. Curr Pharm Design 2004; 10:3195-3211.
  13. Chan J, Flynn J. The immunological aspects of latency in tuberculosis. Clin Immunol 2004; 110:2-12.
  14. Smith CV, Sharma V, Sacchettini JC. TB drug discovery: addressing issues of persistence and resistance. Tuberculosis (Edinb) 2004; 84:45-55.
  15. Zhang Y, Amzel LM. Tuberculosis drug targets. Curr Drug Targets 2002; 3:131-154.
  16. Terwilliger TC, Park MS, Waldo GS, et al. The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology. Tuberculosis (Edinb) 2003; 83:223-249.
  17. Gomez JE, McKinney JD. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis (Edinb) 2004; 84:29-44.
  18. Honer Zu Bentrup K, Miczak A, Swenson DL, Russell DG. Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis. J Bacteriol 1999; 181:7161-7167.
  19. McKinney JD, Honer Zu Bentrup K, Munoz-Elias EJ, et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000; 406:735-738.
  20. Glickman MS, Cox JS, Jacobs WR Jr. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 2000; 5:717-727.
  21. Yuan Y, Lee RE, Besra GS, Belisle JT, Barry CE. Identification of a gene involved in the biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 1995; 92:6630-6634.
  22. Cox JS, Chen B, McNeil M, Jacobs WR Jr. Complex lipid determines tissue- specific replication of Mycobacterium tuberculosis in mice. Nature 1999; 402:79-83.
  23. Gurcha SS, Baulard AR, Kremer L, et al. Ppm1, a novel polyprenol monophosphomannose synthase from Mycobacterium tuberculosis. Biochem J 2002; 365:441-450.
  24. Alexander DC, Jones JR, Tan T, Chen JM, Liu J. PimF, a mannosyltransferase of mycobacteria, is involved in the biosynthesis of phosphatidylinositol mannosides and lipoarabinomannan. J Biol Chem 2004; 279:18824-18833.
  25. Ma Y, Stern RJ, Scherman MS, et al. Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob Agents Chemother 2001; 45:1407-1416.
  26. Almrud JJ, Oliveira MA, Kern AD, Grishin NV, Phillips MA, Hackert ML. Crystal structure of human ornithine decarboxylase at 2.1 A resolution: structural insights to antizyme binding. J Mol Biol 2000; 295:7-16.
  27. Clements JM, Beckett RP, Brown A, et al. Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor. Antimicrob Agents Chemother 2001; 45:563-570.
  28. Khuller GK, Kapur M, Sharma S. Liposome technology for drug delivery against mycobacterial infections. Curr Pharm Design 2004; 10:3263-3274.
  29. Deol P, Khuller GK, Joshi K. Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice. Antimicrob Agents Chemother 1997; 41:1211-1214.
  30. Adams LB, Sinha I, Franzblau SG, Krahenbuhl JL, Mehta RT. Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine. Antimicrob Agents Chemother 1999; 43:1638-1643.
  31. Dhillon J, Fielding R, Adler-Moore J, Goodall RL, Mitchison D. The activity of low-clearance liposomal amikacin in experimental murine tuberculosis. J Antimicrob Chemother 2001; 48:869-876.
  32. Whitehead TC, Lovering AM, Cropley IM, Wade P, Davidson RN. Kinetics and toxicity of liposomal and conventional amikacin in a patient with multidrug-resistant tuberculosis. Eur J Clin Microbiol Infect Dis 1998; 17:794-797.
  33. Quenelle DC, Staas JK, Winchester GA, Barrow EL, Barrow WW. Efficacy of microencapsulated rifampin in Mycobacterium tuberculosis-infected mice. Antimicrob Agents Chemother 1999; 43:1144-1151.
  34. Quenelle DC, Winchester GA, Staas JK, Barrow EL, Barrow WW. Treatment of tuberculosis using a combination of sustained-release rifampin-loaded microspheres and oral dosing with isoniazid. Antimicrob Agents Chemother 2001; 45:1637-1644.
  35. Pandey R, Khuller GK. Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model. J Antimicrob Chemother 2004; 54:266-268.
  36. Suarez S, O’Hara P, Kazantseva M, et al. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model. Pharm Res 2001; 18:1315-1319.
  37. Barrow WW. Microsphere technology for chemotherapy of mycobacterial infections. Curr Pharm Design 2004; 10:3275-3284.
  38. Schumann G, Mollmann U. Screening system for xenosiderophores as potential drug delivery agents in mycobacteria. Antimicrob Agents Chemother 2001; 45:1317-1322.
  39. Tomioka H. Profiles of cytokine network in the hosts with mycobacterial infection. Clin Immunol (Tokyo) 2001; 35:571-579.
  40. Tomioka H. Adjunctive immunotherapy of mycobacterial infections. Curr Pharm Design 2004; 10:3297-3312.
  41. Van de Vosse E, Hoeve MA, Ottenhoff TH. Human genetics of intracellular infectious diseases: molecular and cellular immunity against Mycobacteria and Salmonellae. Lancet Infect Dis 2004; 4:739-749.
  42. Murray HW. Interferon-gamma and host antimicrobial defense: current and future clinical applications. Am J Med 1994; 97:459-467.
  43. Toossi Z. Adjunctive immunotherapy of tuberculosis. Cytokine Cell Mol Ther 1998; 4:105-112.
  44. Holland SM. Cytokine therapy of mycobacterial infections. Adv Intern Med 2000; 45:431-452.
  45. Condos R, Rom WN, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 1997; 349:1513-1515.
  46. Johnson B, Bekker LG, Ress S, Kaplan G. Recombinant interleukin 2 adjunctive therapy in multidrug-resistant tuberculosis. Novartis Found Symp 1998; 217:99-106.
  47. Johnson BJ, Ssekasanvu E, Okwera A, et al. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168:185-191.
  48. Pedral-Sampaio DB, Netto EM, Brites C, et sl. Use of Rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial. Braz J Infect Dis 2003; 7:245-252.
  49. Kemper CA, Bermudez LE, Deresinski SC. Immunomodulatory treatment of Mycobacterium avium complex bacteremia in patients with AIDS by use of recombinant granulocyte-macrophage colony-stimulating factor. J Infect Dis 1998; 177:914-920.
  50. Zhang M, Gong J, Iyer D, et al. T-cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest 1994; 4:2435-2440.
  51. Doherty TM, Sher A. IL-12 promotes drug-induced clearance of Mycobacterium avium infection in mice. J Immunol 1998; 160:5428-5435.
  52. Bermudez LE, Petrofsky M, Wu M, Young LS. Clarithromycin significantly improves interleukin-12-mediated anti-Mycobacterium avium activity and abolishes toxicity in mice. J Infect Dis 1998; 178:896-899.
  53. Alzeer AH, FitzGerald JM. Corticosteroids and tuberculosis: risks and use as adjunctive therapy. Tuber Lung Dis 1993; 74:6-11.
  54. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Database Syst Rev 2000; 3:CD002244.
  55. Hernandez-Pando R, Aguilar-Leon D, Orozco H, et al. 16a- Bromoepiandrosterone restores T helper cell type 1 activity and accelerates chemotherapy-induced bacterial clearance in a model of progressive pulmonary tuberculosis. J Infect Dis 2005; 191:299-306.
  56. Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995; 1:384-397.
  57. Schoeman JF, Springer P, Ravenscroft A, et al. Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role. J Child Neurol 2000; 15:497-503.
  58. Tsenova L, Mangaliso B, Muller G, et al. Use of IMiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrob Agents Chemother 2002; 46:1887-1895.
  59. Reimold AM. TNF-a as therapeutic target: new drugs, more applications. Curr Drug Targets Inflamm Allergy 2002; 1:377-392.
  60. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345:1098-1104.
  61. Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS. ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 1997; 7:433-444.
  62. Tomioka H. ATP-mediated potentiation of antimicrobial activity of macrophages. Clin Immunol (Tokyo) 2003; 40:442-449.
  63. Fairbairn IP, Stober CB, Kumararatne DS, Lammas DA. ATP-mediated killing of intracellular mycobacteria by macrophages is a P2X7-dependent process inducing bacterial death by phagosome-lysosome fusion. J Immunol 2001; 167:3300-3307.
  64. Sikora A, Liu J, Brosnan C, Buell G, Chessel I, Bloom BR. Purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism. J Immunol 1999; 163:558-561.
  65. Kusner DJ, Adams J. ATP-induced killing of virulent Mycobacterium tuberculosis within human macrophages requires phospholipase D. J Immunol 2000; 164:379-388.
  66. Stober CB, Lammas DA, Li CM, Kumararatne DS, Lightman SL, McArdle CA. ATP-mediated killing of Mycobacterium bovis Bacille Calmette-Guerin within human macrophage is calcium dependent and associated with the acidification of mycobacteria-containing phagosomes. J Immunol 2001; 166:6276-6286.
  67. Chackerian A, Alt J, Perera V, Behar SM. Activation of NKT cells protects mice from tuberculosis. Infect Immun 2002; 70:6302-6309.
  68. Burdin N, Brossay L, Kronenberg M. Immunization with galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur J Immunol 1999; 29:2014-2025.
  69. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000; 355:618-621.
  70. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998; 66:5314-5321.
  71. Waters WR, Palmer MV, Nonnecke BJ, Whipple DL, Horst RL. Mycobacterium bovis infection of vitamin D-deficient NOS2-/- mice. Microb Pathog 2004; 36:11-17.
  72. Stanford JL, Stanford CA. Immunotherapy of tuberculosis with Mycobacterium vaccae NCTC 11659. Immunobiology 1994; 191:555-563.
  73. Stanford J, Stanford C, Grange J. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis. Front Biosci 2004; 9:1701-1719.
  74. Mwinga A, Nunn A, Ngwira B. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. Lancet 2002; 360:1050-1055.
  75. De Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Detabase Syst Rev 2003; CD001166.
  76. Chandra RK. Nutrient supplementation as adjunct therapy in pulmonary tuberculosis. Int J Vitam Nutr Res 2004; 74:144-146.
  77. Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting. Am J Clin Nutr 2004; 80:460-465.
  78. Tomioka H. Present status and future prospects of chemotherapeutics for intractable infections due to Mycobacterium avium complex. Curr Drug Discovery Technol 2004; 1;255-268.
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