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The Medicinal Chemistry of Tuberculosis Chemotherapy

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Third World Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 7))

Abstract

The development of effective chemotherapy for the treatment of tuberculosis (TB) began in the 1940s and has been reinvigorated recently due to concern regarding the emergence of highly drug-resistant TB strains. This chapter explores the medicinal chemistry efforts that gave rise to current frontline and second-line drugs in global use today and attempts to comprehensively summarize ongoing discovery and lead optimization programs being conducted in both the private and the public sector. TB has a large number of disease-specific considerations and constraints that introduce significant complexity in drug discovery efforts. Conceptually, the disease encompasses all the drug discovery challenges of both infectious diseases and oncology, and integrating these considerations into programs that often demand collaboration between industry and academia is both challenging and rewarding.

This work was funded in part by the Division for Intramural Research, NIAID.

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References

  1. Dye C, Lonnroth K, Jaramillo E, Williams BG, Raviglione M (2009) Trends in tuberculosis incidence and their determinants in 134 countries. Bull World Health Organ 87:683–691

    CAS  Google Scholar 

  2. Barry CE III, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7:845–855

    CAS  Google Scholar 

  3. Young D, Dye C (2006) The development and impact of tuberculosis vaccines. Cell 124:683–687

    CAS  Google Scholar 

  4. Kaufmann SH, Hussey G, Lambert PH (2010) New vaccines for tuberculosis. Lancet 375:2110–2119

    Google Scholar 

  5. Parwati I, van Crevel R, van Soolingen D (2010) Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. Lancet Infect Dis 10:103–111

    Google Scholar 

  6. Dye C, Williams BG (2010) The population dynamics and control of tuberculosis. Science 328:856–861

    CAS  Google Scholar 

  7. Iseman MD (2002) Tuberculosis therapy: past, present and future. Eur Respir J Suppl 36:87s–94s

    CAS  Google Scholar 

  8. Murray JF (2004) A century of tuberculosis. Am J Respir Crit Care Med 169:1181–1186

    Google Scholar 

  9. Thoren M, Hinshaw HC (1952) Therapy of pulmonary tuberculosis with isoniazid alone and in combination with streptomycin and with para-amino-salicylic acid. Stanford Med Bull 10:316–318

    CAS  Google Scholar 

  10. Marshall G (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2:769–782

    Google Scholar 

  11. Youmans GP, Raleigh GW, Youmans AS (1947) The tuberculostatic action of para-aminosalicylic acid. J Bacteriol 54:409–416

    CAS  Google Scholar 

  12. Graessle OE, Pietrowski JJ (1949) The in vitro effect of para-aminosalicylic acid (PAS) in preventing acquired resistance to streptomycin by Mycobacterium tuberculosis. J Bacteriol 57:459–464

    CAS  Google Scholar 

  13. Dooneief AS, Buchberg A, Steinbach MM (1950) Para-aminosalicylic acid (PAS) in chronic pulmonary tuberculosis. N Engl J Med 242:859–862

    CAS  Google Scholar 

  14. Bowen DA, Collins DM (1952) Development of drug resistance to isoniazid in cases of pulmonary tuberculosis. Tubercle 33:276–278

    CAS  Google Scholar 

  15. Joiner CL, Maclean KS, Carroll JD, Marsh K, Collard P, Knox R (1954) Isoniazid and P. A. S. in chronic pulmonary tuberculosis: a warning. Lancet 267:663–666

    CAS  Google Scholar 

  16. Marshall G (1955) Various combinations of isoniazid with streptomycin or with P.A.S. in the treatment of pulmonary tuberculosis; seventh report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Br Med J 1:435–445

    Google Scholar 

  17. Capon AW (1954) Streptomycin and PAS vs. streptomycin, PAS and isoniazid in the treatment of pulmonary tuberculosis. Can Med Assoc J 70:62–67

    CAS  Google Scholar 

  18. Hudgins PC, Patnode RA, Cummings MM (1955) The effect of cycloserine on growing and resting tubercle bacilli. Am Rev Tuberc 72:685–686

    CAS  Google Scholar 

  19. Hutton PW, Tonkin IM (1960) Ethionamide (1314') with streptomycin in acute tuberculosis of recent origin in Uganda Africans: a pilot study. Tubercle 41:253–256

    CAS  Google Scholar 

  20. Bartz QR, Ehrlich J, Mold JD, Penner MA, Smith RM (1951) Viomycin, a new tuberculostatic antibiotic. Am Rev Tuberc 63:4–6

    CAS  Google Scholar 

  21. Patnode RA, Hudgins PC (1958) Effect of kanamycin on Mycobacterium tuberculosis in vitro. Am Rev Tuberc 78:138–139

    CAS  Google Scholar 

  22. Kaida K, Sugiyama K (1959) Clinical experience with PZA-INH therapy: report on study of resected specimens following the above therapy in particular. Dis Chest 36:378–388

    CAS  Google Scholar 

  23. Somner AR, Brace AA (1962) Ethionamide, pyrazinamide and cycloserine used successfully in the treatment of chronic pulmonary tuberculosis. Tubercle 43:345–360

    CAS  Google Scholar 

  24. Tuberculosis Chemotherapy Center M (1959) A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 21:51–144

    Google Scholar 

  25. Bienenstock J, Shaldon S (1963) Thiacetazone in tuberculosis. Lancet 2:817–818

    CAS  Google Scholar 

  26. Cuthbert J, Bruce LG (1964) Treatment of pulmonary tuberculosis by capreomycin and PAS: a small preliminary trial. Tubercle 45:205–210

    CAS  Google Scholar 

  27. (2008) Clofazimine. Tuberculosis (Edinb) 88:96–99

    Google Scholar 

  28. Doster B, Murray FJ, Newman R, Woolpert SF (1973) Ethambutol in the initial treatment of pulmonary tuberculosis. U.S. Public Health Service tuberculosis therapy trials. Am Rev Respir Dis 107:177–190

    CAS  Google Scholar 

  29. Lees AW, Tyrrell WF, Smith J, Allan GW (1970) Ethambutol in the retreatment of chronic pulmonary tuberculosis. Br J Dis Chest 64:85–89

    CAS  Google Scholar 

  30. Fisher L (1971) Rifampin–new and potent drug for TB treatment. Bull Natl Tuberc Respir Dis Assoc 57:11–12

    CAS  Google Scholar 

  31. Mitchison DA (2005) The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med 171:699–706

    Google Scholar 

  32. (1974) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report. East African-British Medical Research Councils. Lancet 2:237–240

    Google Scholar 

  33. McCune RM Jr, Tompsett R (1956) Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J Exp Med 104:737–762

    CAS  Google Scholar 

  34. Grosset J (1978) The sterilizing value of rifampicin and pyrazinamide in experimental short-course chemotherapy. Bull Int Union Tuberc 53:5–12

    CAS  Google Scholar 

  35. (1986) Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council. Am Rev Respir Dis 133:779–783

    Google Scholar 

  36. (1988) Five-year follow-up of a clinical trial of three 6-month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council. Am Rev Respir Dis 137:1147–1150

    Google Scholar 

  37. (1983) Controlled clinical trial of 4 short-couse regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle 64:153–166

    Google Scholar 

  38. (1991) Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis 143:700–706

    Google Scholar 

  39. Bayer R, Wilkinson D (1995) Directly observed therapy for tuberculosis: history of an idea. Lancet 345:1545–1548

    CAS  Google Scholar 

  40. Edlin BR, Tokars JI, Grieco MH, Crawford JT, Williams J, Sordillo EM, Ong KR, Kilburn JO, Dooley SW, Castro KG et al (1992) An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N Engl J Med 326:1514–1521

    CAS  Google Scholar 

  41. Friedman CR, Stoeckle MY, Kreiswirth BN, Johnson WD Jr, Manoach SM, Berger J, Sathianathan K, Hafner A, Riley LW (1995) Transmission of multidrug-resistant tuberculosis in a large urban setting. Am J Respir Crit Care Med 152:355–359

    CAS  Google Scholar 

  42. Bifani PJ, Plikaytis BB, Kapur V, Stockbauer K, Pan X, Lutfey ML, Moghazeh SL, Eisner W, Daniel TM, Kaplan MH, Crawford JT, Musser JM, Kreiswirth BN (1996) Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family. JAMA 275:452–457

    CAS  Google Scholar 

  43. Agerton T, Valway S, Gore B, Pozsik C, Plikaytis B, Woodley C, Onorato I (1997) Transmission of a highly drug-resistant strain (strain W1) of Mycobacterium tuberculosis. Community outbreak and nosocomial transmission via a contaminated bronchoscope. JAMA 278:1073–1077

    CAS  Google Scholar 

  44. (1992) A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin. Hong Kong Chest Service/British Medical Research Council. Tuber Lung Dis 73:59–67

    Google Scholar 

  45. Kohno S, Koga H, Kaku M, Maesaki S, Hara K (1992) Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis. Chest 102:1815–1818

    CAS  Google Scholar 

  46. Sahoo RC (1993) Ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin – a south Indian experience. Tuber Lung Dis 74:140–141

    CAS  Google Scholar 

  47. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, Ngowi FI, Ramsay AR, Saruni AO, Sam N, Tillotson G, Uiso LO, Yates M, Gillespie SH (1996) Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 22:827–833

    CAS  Google Scholar 

  48. Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR, Marra F (2007) Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs 67:2077–2099

    CAS  Google Scholar 

  49. Bergmann JS, Woods GL (1998) In vitro activity of antimicrobial combinations against clinical isolates of susceptible and resistant Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2:621–626

    CAS  Google Scholar 

  50. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC (2005) Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother 49:2816–2821

    CAS  Google Scholar 

  51. Anger HA, Dworkin F, Sharma S, Munsiff SS, Nilsen DM, Ahuja SD (2010) Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, 2000-06. J Antimicrob Chemother 65:775–783

    CAS  Google Scholar 

  52. Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S (2010) Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 50:49–55

    CAS  Google Scholar 

  53. Barry CE (2010) Linezolid Pharmacokinetics (PK) in Multi-Drug Resistant (MDR) and Extensively-Drug Resistant (XDR) Tuberculosis (TB) (S30PK). Clinical Trial NCT00727844. Sponsored by National Institute for Allergy and Infectious Diseases. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  54. MacKenzie WR (2010) Linezolid to treat extensively drug-resistant tuberculosis. Clinical Trial NCT00691392. Sponsored by the Centers for Disease Control. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  55. Ross JD, Horne NW, Grant IW, Crofton JW (1958) Hospital treatment of pulmonary tuberculosis; a follow-up study of patients admitted to Edinburgh hospitals in 1953. Br Med J 1:237–242

    CAS  Google Scholar 

  56. Caminero JA, Sotgiu G, Zumla A, Migliori GB (2010) Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 10:621–629

    CAS  Google Scholar 

  57. Centers for Disease Control and Prevention (2006) Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs–worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep 55:301–305

    Google Scholar 

  58. Kwon YS, Kim YH, Suh GY, Chung MP, Kim H, Kwon OJ, Choi YS, Kim K, Kim J, Shim YM, Koh WJ (2008) Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis 47:496–502

    Google Scholar 

  59. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB (2010) Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 51:6–14

    Google Scholar 

  60. Dheda K, Shean K, Zumla A, Badri M, Streicher EM, Page-Shipp L, Willcox P, John MA, Reubenson G, Govindasamy D, Wong M, Padanilam X, Dziwiecki A, van Helden PD, Siwendu S, Jarand J, Menezes CN, Burns A, Victor T, Warren R, Grobusch MP, van der Walt M, Kvasnovsky C (2010) Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet 375:1798–1807

    Google Scholar 

  61. Migliori GB, Sotgiu G, D'Arcy Richardson M, Centis R, Facchini A, Guenther G, Spanevello A, Lange C (2009) MDR-TB and XDR-TB: drug resistance and treatment outcomes. Eur Respir J 34:778–779

    CAS  Google Scholar 

  62. Jeon DS, Kim DH, Kang HS, Hwang SH, Min JH, Kim JH, Sung NM, Carroll MW, Park SK (2009) Survival and predictors of outcomes in non-HIV-infected patients with extensively drug-resistant tuberculosis. Int J Tuberc Lung Dis 13:594–600

    CAS  Google Scholar 

  63. Velayati AA, Farnia P, Masjedi MR, Ibrahim TA, Tabarsi P, Haroun RZ, Kuan HO, Ghanavi J, Varahram M (2009) Totally drug-resistant tuberculosis strains: evidence of adaptation at the cellular level. Eur Respir J 34:1202–1203

    CAS  Google Scholar 

  64. Velayati AA, Masjedi MR, Farnia P, Tabarsi P, Ghanavi J, Ziazarifi AH, Hoffner SE (2009) Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 136:420–425

    Google Scholar 

  65. Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, Vernon A, Lienhardt C, Burman W (2009) Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med 6:e1000146

    Google Scholar 

  66. Zhou SF, Xue CC, Yu XQ, Li C, Wang G (2007) Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 29:687–710

    CAS  Google Scholar 

  67. Finch CK, Chrisman CR, Baciewicz AM, Self TH (2002) Rifampin and rifabutin drug interactions: an update. Arch Intern Med 162:985–992

    CAS  Google Scholar 

  68. Davies G, Cerri S, Richeldi L (2007) Rifabutin for treating pulmonary tuberculosis. Cochrane Database Syst Rev:CD005159

    Google Scholar 

  69. Peloquin CA (2001) Pharmacological issues in the treatment of tuberculosis. Ann NY Acad Sci 953:157–164

    CAS  Google Scholar 

  70. Sen T, Joshi SR, Udwadia ZF (2009) Tuberculosis and diabetes mellitus: merging epidemics. J Assoc Physicians India 57:399–404

    Google Scholar 

  71. Peloquin CA (2002) Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 62:2169–2183

    CAS  Google Scholar 

  72. Mitchison DA (2000) Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 4:796–806

    CAS  Google Scholar 

  73. Herbert D, Paramasivan CN, Venkatesan P, Kubendiran G, Prabhakar R, Mitchison DA (1996) Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis. Antimicrob Agents Chemother 40:2296–2299

    CAS  Google Scholar 

  74. Garcia-Tapia A, Rodriguez JC, Ruiz M, Royo G (2004) Action of fluoroquinolones and linezolid on logarithmic- and stationary-phase culture of Mycobacterium tuberculosis. Chemotherapy 50:211–213

    CAS  Google Scholar 

  75. Wayne LG, Sohaskey CD (2001) Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol 55:139–163

    CAS  Google Scholar 

  76. Xie Z, Siddiqi N, Rubin EJ (2005) Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 49:4778–4780

    CAS  Google Scholar 

  77. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K (2002) Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43:717–731

    CAS  Google Scholar 

  78. Dartois V, Barry CE (2010) Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Curr Clin Pharmacol 5:96–114

    CAS  Google Scholar 

  79. Via LE, Lin PL, Ray SM, Carrillo J, Allen SS, Eum SY, Taylor K, Klein E, Manjunatha U, Gonzales J, Lee EG, Park SK, Raleigh JA, Cho SN, McMurray DN, Flynn JL, Barry CE III (2008) Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76:2333–2340

    CAS  Google Scholar 

  80. Sensi P (1983) History of the development of rifampin. Rev Infect Dis 5(Suppl 3):S402–406

    CAS  Google Scholar 

  81. Lancini G, Zanichelli W (1977) Structure-activity relationships in rifamycins. In: Perlman D (ed) Structure-activity relationships among the semisynthetic antibiotics. Academic, New York, pp 531–600

    Google Scholar 

  82. Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA (2001) Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 104:901–912

    CAS  Google Scholar 

  83. Floss HG, Yu TW (2005) Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev 105:621–632

    CAS  Google Scholar 

  84. Baysarowich J, Koteva K, Hughes DW, Ejim L, Griffiths E, Zhang K, Junop M, Wright GD (2008) Rifamycin antibiotic resistance by ADP-ribosylation: structure and diversity of Arr. Proc Natl Acad Sci USA 105:4886–4891

    CAS  Google Scholar 

  85. Li AP, Reith MK, Rasmussen A, Gorski JC, Hall SD, Xu L, Kaminski DL, Cheng LK (1997) Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Chem Biol Interact 107:17–30

    CAS  Google Scholar 

  86. Narita M, Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D (2000) Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis 30:779–783

    CAS  Google Scholar 

  87. Fox HH (1952) The chemical approach to the control of tuberculosis. Science 116:129–134

    CAS  Google Scholar 

  88. Kakimoto S, Tone I (1965) Antituberculous compounds. 23. Alkyl- and acylisonicotinic acid hydrazides. J Med Chem 8:868

    CAS  Google Scholar 

  89. Fox HH (1953) The chemical attack on tuberculosis. Trans NY Acad Sci 15:234–242

    CAS  Google Scholar 

  90. Rubbo SD, Edgar J, Vaughan G (1957) Chemotherapy of tuberculosis. I. Antituberculous activity of verazide and related hydrazones. Am Rev Tuberc 76:331–345

    CAS  Google Scholar 

  91. Rubbo SD, Rouch LC, Egan JB, Waddington AL, Tellesson WG (1958) Chemotherapy of tuberculosis. III. Verazide in the treatment of pulmonary tuberculosis. Am Rev Tuberc 78:251–258

    CAS  Google Scholar 

  92. Wayne LG, Sramek HA (1994) Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob Agents Chemother 38:2054–2058

    CAS  Google Scholar 

  93. Vilcheze C, Jacobs WR Jr (2007) The mechanism of isoniazid killing: clarity through the scope of genetics. Annu Rev Microbiol 61:35–50

    CAS  Google Scholar 

  94. Rozwarski DA, Grant GA, Barton DH, Jacobs WR Jr, Sacchettini JC (1998) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98–102

    CAS  Google Scholar 

  95. Rawat R, Whitty A, Tonge PJ (2003) The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci USA 100:13881–13886

    CAS  Google Scholar 

  96. Argyrou A, Jin L, Siconilfi-Baez L, Angeletti RH, Blanchard JS (2006) Proteome-wide profiling of isoniazid targets in Mycobacterium tuberculosis. Biochemistry 45:13947–13953

    CAS  Google Scholar 

  97. Rist N, Grumbach F, Libermann D (1959) Experiments on the antituberculous activity of alpha-ethylthioisonicotinamide. Am Rev Tuberc 79:1–5

    CAS  Google Scholar 

  98. Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Jr, Sacchettini JC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204:73–78

    CAS  Google Scholar 

  99. DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE III (2000) Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci USA 97:9677–9682

    CAS  Google Scholar 

  100. Domagk G (1950) Investigations on the antituberculous activity of the thiosemicarbazones in vitro and in vivo. Am Rev Tuberc 61:8–19

    CAS  Google Scholar 

  101. Behnisch R, Mietzsch F, Schmidt H (1950) Chemical studies on thiosemicarbazones with particular reference to antituberculous activity. Am Rev Tuberc 61:1–7

    CAS  Google Scholar 

  102. Alahari A, Trivelli X, Guerardel Y, Dover LG, Besra GS, Sacchettini JC, Reynolds RC, Coxon GD, Kremer L (2007) Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria. PLoS ONE 2:e1343

    Google Scholar 

  103. Alahari A, Alibaud L, Trivelli X, Gupta R, Lamichhane G, Reynolds RC, Bishai WR, Guerardel Y, Kremer L (2009) Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis. Mol Microbiol 71:1263–1277

    CAS  Google Scholar 

  104. Lawn SD, Frimpong EH, Acheampong JW (1999) Life-threatening cutaneous reactions to thiacetazone-containing antituberculosis treatment in Kumasi, Ghana. West Afr J Med 18:249–253

    CAS  Google Scholar 

  105. Mc Kenzie D, Malone L (1948) The effect of nicotinic acid amide on experimental tuberculosis of white mice. J Lab Clin Med 33:1249–1253

    CAS  Google Scholar 

  106. Rogers EF, Leanza WJ, Becker HJ, Matzuk AR, O'Neill RC, Basso AJ, Stein GA, Solotorovsky M, Gregory FJ, Pfister K III (1952) Antitubercular diazine carboxamides. Science 116:253–254

    CAS  Google Scholar 

  107. Kushner S, Dalalian H, Sanjurjo JL, Bach FL, Safir SR, Smith VK, Williams JH (1952) Experimental chemotherapy of tuberculosis. 2. The synthesis of pyrazinamides and related compounds. J Am Chem Soc 74:3617–3621

    CAS  Google Scholar 

  108. Felder E, Pitre D, Tiepolo U (1962) N-Morpholinomethyl-pyrazinamide: chemico-physical characteristics and determination in biological fluids. Minerva Med 53:1699–1703

    CAS  Google Scholar 

  109. Chung WJ, Kornilov A, Brodsky BH, Higgins M, Sanchez T, Heifets LB, Cynamon MH, Welch J (2008) Inhibition of M. tuberculosis in vitro in monocytes and in mice by aminomethylene pyrazinamide analogs. Tuberculosis (Edinb) 88:410–419

    CAS  Google Scholar 

  110. Scorpio A, Zhang Y (1996) Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat Med 2:662–667

    CAS  Google Scholar 

  111. Boshoff HI, Mizrahi V (2000) Expression of Mycobacterium smegmatis pyrazinamidase in Mycobacterium tuberculosis confers hypersensitivity to pyrazinamide and related amides. J Bacteriol 182:5479–5485

    CAS  Google Scholar 

  112. Boshoff HI, Mizrahi V, Barry CE III (2002) Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I. J Bacteriol 184:2167–2172

    CAS  Google Scholar 

  113. Zimhony O, Cox JS, Welch JT, Vilcheze C, Jacobs WR Jr (2000) Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med 6:1043–1047

    CAS  Google Scholar 

  114. Epstein IG, Nair KG, Boyd LJ (1956) The treatment of human pulmonary tuberculosis with cycloserine: progress report. Dis Chest 29:241–257

    CAS  Google Scholar 

  115. Kim MG, Strych U, Krause K, Benedik M, Kohn H (2003) N(2)-substituted D, L-cycloserine derivatives: synthesis and evaluation as alanine racemase inhibitors. J Antibiot (Tokyo) 56:160–168

    CAS  Google Scholar 

  116. Neuhaus F (1967) D-cycloserine and O-carbamoyl-D-serine. In: Gottlieb D, Shaw P (eds) Antibiotics I (mode of action) pp 40-83. Springer-Verlag, New York

    Google Scholar 

  117. Peisach D, Chipman DM, Van Ophem PW, Manning JM, Ringe D (1998) D-cycloserine inactivation of D-amino acid aminotransferase leads to a stable noncovalent protein complex with an aromatic cycloserine-PLP derivative. J Am Chem Soc 120:2268–2274

    CAS  Google Scholar 

  118. Feng Z, Barletta RG (2003) Roles of Mycobacterium smegmatis D-alanine:D-alanine ligase and D-alanine racemase in the mechanisms of action of and resistance to the peptidoglycan inhibitor D-cycloserine. Antimicrob Agents Chemother 47:283–291

    CAS  Google Scholar 

  119. Lehmann J (1949) The treatment of tuberculosis in Sweden with para-aminosalicylic acid: a review. Dis Chest 16:684–703, illust

    CAS  Google Scholar 

  120. Doub L, Schaefer JJ, Bambas LL, Walker CT (1951) Some derivatives of 4-amino-2-hydroxybenzoic acid (para-aminosalicylic acid). J Am Chem Soc 73:903–906

    CAS  Google Scholar 

  121. Rengarajan J, Sassetti CM, Naroditskaya V, Sloutsky A, Bloom BR, Rubin EJ (2004) The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol 53:275–282

    CAS  Google Scholar 

  122. Nomoto S, Shiba T (1977) Chemical studies on tuberactinomycin. XIII. Modification of beta-ureidodehydroalanine residue in tuberactinomycin N. J Antibiot (Tokyo) 30:1008–1011

    CAS  Google Scholar 

  123. Linde RG, Birsner NC, Chandrasekaran RY, Clancy J, Howe RJ, Lyssikatos JP, MacLelland CP, Magee TV, Petitpas JW, Rainville JP, Su WG, Vu CB, Whipple DA (1997) Cyclic homopentapeptides.3. Synthetic modifications to the capreomycins and tuberactinomycins: compounds with activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. Bioorg Med Chem Lett 7:1149–1152

    CAS  Google Scholar 

  124. Stanley RE, Blaha G, Grodzicki RL, Strickler MD, Steitz TA (2010) The structures of the anti-tuberculosis antibiotics viomycin and capreomycin bound to the 70S ribosome. Nat Struct Mol Biol 17:289–293

    CAS  Google Scholar 

  125. Kotra LP, Haddad J, Mobashery S (2000) Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob Agents Chemother 44:3249–3256

    CAS  Google Scholar 

  126. Ramaswamy S, Musser JM (1998) Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79:3–29

    CAS  Google Scholar 

  127. Bottger EC, Springer B (2008) Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr 167:141–148

    Google Scholar 

  128. Suzuki Y, Katsukawa C, Tamaru A, Abe C, Makino M, Mizuguchi Y, Taniguchi H (1998) Detection of kanamycin-resistant Mycobacterium tuberculosis by identifying mutations in the 16S rRNA gene. J Clin Microbiol 36:1220–1225

    CAS  Google Scholar 

  129. Okamoto S, Tamaru A, Nakajima C, Nishimura K, Tanaka Y, Tokuyama S, Suzuki Y, Ochi K (2007) Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria. Mol Microbiol 63:1096–1106

    CAS  Google Scholar 

  130. Magnet S, Blanchard JS (2005) Molecular insights into aminoglycoside action and resistance. Chem Rev 105:477–498

    CAS  Google Scholar 

  131. Zaunbrecher MA, Sikes RD Jr, Metchock B, Shinnick TM, Posey JE (2009) Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 106:20004–20009

    CAS  Google Scholar 

  132. Ramon-Garcia S, Martin C, De Rossi E, Ainsa JA (2007) Contribution of the Rv2333c efflux pump (the Stp protein) from Mycobacterium tuberculosis to intrinsic antibiotic resistance in Mycobacterium bovis BCG. J Antimicrob Chemother 59:544–547

    CAS  Google Scholar 

  133. Peloquin CA, Berning SE, Nitta AT, Simone PM, Goble M, Huitt GA, Iseman MD, Cook JL, Curran-Everett D (2004) Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 38:1538–1544

    CAS  Google Scholar 

  134. (2008) Handbook of anti-tuberculosis agents. Introduction. Tuberculosis (Edinb) 88:85–86

    Google Scholar 

  135. Lamp KC, Freeman CD, Klutman NE, Lacy MK (1999) Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 36:353–373

    CAS  Google Scholar 

  136. Barry CE III, Boshoff HI, Dowd CS (2004) Prospects for clinical introduction of nitroimidazole antibiotics for the treatment of tuberculosis. Curr Pharm Des 10:3239–3262

    CAS  Google Scholar 

  137. Cavalleri B, Ballotta R, Arioli V, Lancini G (1973) New 5-substituted 1-alkyl-2-nitroimidazoles. J Med Chem 16:557–560

    CAS  Google Scholar 

  138. Roe FJ (1977) Metronidazole: review of uses and toxicity. J Antimicrob Chemother 3:205–212

    CAS  Google Scholar 

  139. Bendesky A, Menendez D, Ostrosky-Wegman P (2002) Is metronidazole carcinogenic? Mutat Res 511:133–144

    CAS  Google Scholar 

  140. Ashtekar DR, Costa-Perira R, Nagrajan K, Vishvanathan N, Bhatt AD, Rittel W (1993) In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 37:183–186

    CAS  Google Scholar 

  141. Barry CE III, Blanchard JS (2010) The chemical biology of new drugs in the development for tuberculosis. Curr Opin Chem Biol 14:456–466

    CAS  Google Scholar 

  142. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR (2000) A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405:962–966

    CAS  Google Scholar 

  143. Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H, Shimokawa Y, Komatsu M (2006) OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 3:e466

    Google Scholar 

  144. Papadopoulou MV, Bloomer WD, McNeil MR (2007) NLCQ-1 and NLCQ-2, two new agents with activity against dormant Mycobacterium tuberculosis. Int J Antimicrob Agents 29:724–727

    CAS  Google Scholar 

  145. Kim P, Zhang L, Manjunatha UH, Singh R, Patel S, Jiricek J, Keller TH, Boshoff HI, Barry CE III, Dowd CS (2009) Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles. J Med Chem 52:1317–1328

    CAS  Google Scholar 

  146. Palmer BD, Thompson AM, Sutherland HS, Blaser A, Kmentova I, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA (2010) Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2, 1-b][1,3]oxazine (PA-824). J Med Chem 53:282–294

    CAS  Google Scholar 

  147. Sutherland HS, Blaser A, Kmentova I, Franzblau SG, Wan B, Wang Y, Ma Z, Palmer BD, Denny WA, Thompson AM (2010) Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains. J Med Chem 53:855–866

    CAS  Google Scholar 

  148. Kim P, Kang S, Boshoff HI, Jiricek J, Collins M, Singh R, Manjunatha UH, Niyomrattanakit P, Zhang L, Goodwin M, Dick T, Keller TH, Dowd CS, Barry CE III (2009) Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships. J Med Chem 52:1329–1344

    CAS  Google Scholar 

  149. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE III (2008) PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 322:1392–1395

    CAS  Google Scholar 

  150. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, Daniels L, Dick T, Pang SS, Barry CE III (2006) Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103:431–436

    CAS  Google Scholar 

  151. (2008) Pa-824. Tuberculosis (Edinb) 88:134–136

    Google Scholar 

  152. Manjunatha U, Boshoff HI, Barry CE (2009) The mechanism of action of PA-824: novel insights from transcriptional profiling. Commun Integr Biol 2:215–218

    CAS  Google Scholar 

  153. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, Bishai W, Grosset J (2005) Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents Chemother 49:2289–2293

    CAS  Google Scholar 

  154. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, Grosset JH (2008) Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother 52:1522–1524

    CAS  Google Scholar 

  155. Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK (2009) Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob Agents Chemother 53:3720–3725

    CAS  Google Scholar 

  156. Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK (2009) Assessment of the effects of the nitroimidazo-oxazine PA-824 on renal function in healthy subjects. Antimicrob Agents Chemother 53:3726–3733

    CAS  Google Scholar 

  157. Dawson R, Diacon A (2010) A phase IIa trial to evaluate the safety, tolerability, extended early bactericidal activity and pharmacokinetics of 14 days' treatment with four oral doses of PA-824 in adult participants with newly diagnosed, uncomplicated, smear-positive, pulmonary tuberculosis. In: PA-824-CL-007: phase IIa evaluation of early bactericidal activity in pulmonary tuberculosis. Clinical Trial NCT00567840. Sponsored by the Global Alliance for TB Drug Development. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  158. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, Donald PR, van Niekerk C, Whitney K, Rouse DJ, Laurenzi MW, Ginsberg AM, Spigelman MK (2010) Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother 54:3402–3407

    CAS  Google Scholar 

  159. Sasaki H, Haraguchi Y, Itotani M, Kuroda H, Hashizume H, Tomishige T, Kawasaki M, Matsumoto M, Komatsu M, Tsubouchi H (2006) Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. J Med Chem 49:7854–7860

    CAS  Google Scholar 

  160. Saliu OY, Crismale C, Schwander SK, Wallis RS (2007) Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis. J Antimicrob Chemother 60:994–998

    CAS  Google Scholar 

  161. van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE (2009) New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development. Antimicrob Agents Chemother 53:849–862

    Google Scholar 

  162. Rivers EC, Mancera RL (2008) New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem 15:1956–1967

    CAS  Google Scholar 

  163. Diacon, AH, Rustomjee, R, Dawson R (2007) A phase 2, multi-center, non-controlled, open-label dose escalation trial to assess the safety, tolerability, pharmacokinetics, and efficacy of orally administered OPC-67683 two times daily to patients with pulmonary multidrug-resistant tuberculosis refractory to conventional treatment. In: Safety and pharmacokinetics (PK) in multidrug-resistant (MDR) refractive tuberculosis. Clinical Trial NCT01131351. Sponsored by Otsuka Pharmaceutical Development and Commercialization, Inc. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  164. Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, Williams P, de Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-Pernot C, Lounis N, Jarlier V (2005) A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307:223–227

    CAS  Google Scholar 

  165. Matteelli A, Carvalho AC, Dooley KE, Kritski A (2010) TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol 5:849–858

    CAS  Google Scholar 

  166. Arjona A (2008) TMC-207 mycobacterial ATP synthase inhibitor treatment of tuberculosis. Drugs Future 33:1018–1024

    CAS  Google Scholar 

  167. Upadhayaya RS, Vandavasi JK, Kardile RA, Lahore SV, Dixit SS, Deokar HS, Shinde PD, Sarmah MP, Chattopadhyaya J (2010) Novel quinoline and naphthalene derivatives as potent antimycobacterial agents. Eur J Med Chem 45:1854–1867

    CAS  Google Scholar 

  168. Upadhayaya RS, Vandavasi JK, Vasireddy NR, Sharma V, Dixit SS, Chattopadhyaya J (2009) Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against Mycobacterium tuberculosis. Bioorg Med Chem 17:2830–2841

    CAS  Google Scholar 

  169. Gaurrand S, Desjardins S, Meyer C, Bonnet P, Argoullon JM, Oulyadi H, Guillemont J (2006) Conformational analysis of r207910, a new drug candidate for the treatment of tuberculosis, by a combined NMR and molecular modeling approach. Chem Biol Drug Des 68:77–84

    CAS  Google Scholar 

  170. Petit S, Coquerel G, Meyer C, Guillemont J (2007) Absolute configuration and structural features of R207910, a novel anti-tuberculosis agent. J Mol Struct 837:252–256

    CAS  Google Scholar 

  171. Andries, KJLM, Van Gestel, JFE (2005) Use of substituted quinoline derivatives for the treatment of drug resistant mycobacterial diseases. Johnson & Johnson: United States. WO2005117875

    Google Scholar 

  172. Lounis N, Guillemont J, Veziris N, Koul A, Jarlier V, Andries K (2010) R207910 (TMC207): a new antibiotic for the treatment of tuberculosis. Méd Mal Infect 40:383–390

    CAS  Google Scholar 

  173. Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, Mthiyane TC, De Marez T, van Heeswijk R, Kerstens R, Koul A, De Beule K, Donald PR, McNeeley DF (2008) Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents Chemother 52:2831–2835

    CAS  Google Scholar 

  174. Petrella S, Cambau E, Chauffour A, Andries K, Jarlier V, Sougakoff W (2006) Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother 50:2853–2856

    CAS  Google Scholar 

  175. Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, Ristic Z, Lill H, Dorange I, Guillemont J, Bald D, Andries K (2007) Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol 3:323–324

    CAS  Google Scholar 

  176. de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K (2007) A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910. Proteins 67:971–980

    Google Scholar 

  177. Lounis N, Veziris N, Chauffour A, Truffot-Pernot C, Andries K, Jarlier V (2006) Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration. Antimicrob Agents Chemother 50:3543–3547

    CAS  Google Scholar 

  178. Ibrahim M, Truffot-Pernot C, Andries K, Jarlier V, Veziris N (2009) Sterilizing activity of R207910 (TMC207)-containing regimens in the murine model of tuberculosis. Am J Respir Crit Care Med 180:553–557

    CAS  Google Scholar 

  179. Lenaerts AJ, Hoff D, Aly S, Ehlers S, Andries K, Cantarero L, Orme IM, Basaraba RJ (2007) Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910. Antimicrob Agents Chemother 51:3338–3345

    CAS  Google Scholar 

  180. Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, Gohlmann HW, Willebrords R, Poncelet A, Guillemont J, Bald D, Andries K (2008) Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 283:25273–25280

    CAS  Google Scholar 

  181. Veziris N, Ibrahim M, Lounis N, Chauffour A, Truffot-Pernot C, Andries K, Jarlier V (2009) A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis. Am J Respir Crit Care Med 179:75–79

    CAS  Google Scholar 

  182. Lounis N, Gevers T, Van Den Berg J, Andries K (2008) Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother 52:3568–3572

    CAS  Google Scholar 

  183. Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF (2009) The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 360:2397–2405

    CAS  Google Scholar 

  184. Barry CE III (2009) Unorthodox approach to the development of a new antituberculosis therapy. N Engl J Med 360:2466–2467

    CAS  Google Scholar 

  185. Tibotec-Virco Virology BVBA Clinical Trial (2009) A Phase II, Open-Label Trial With TMC207 as Part of a Multi-drug Resistant Tuberculosis (MDR-TB) Treatment Regimen in Subjects with Sputum Smear-positive Pulmonary Infection with MDR-TB. Clinical Trial NCT00910871. Sponsored by Tibotec BVBA. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  186. Webb S (2009) Public-private partnership tackles TB challenges in parallel. Nat Rev Drug Discov 8:599–600

    CAS  Google Scholar 

  187. Gregory WA (1984) p-Oxazolidinylbenzene compounds as antibacterial agents. E. I. DuPont de Nemours and Company: United States US4461772

    Google Scholar 

  188. Zurenko GE, Yagi BH, Schaadt RD, Allison JW, Kilburn JO, Glickman SE, Hutchinson DK, Barbachyn MR, Brickner SJ (1996) In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother 40:839–845

    CAS  Google Scholar 

  189. Ford CW, Hamel JC, Wilson DM, Moerman JK, Stapert D, Yancey RJ, Hutchinson DK, Barbachyn MR, Brickner SJ (1996) In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections. Antimicrob Agents Chemother 40:1508–1513

    CAS  Google Scholar 

  190. Jones RN, Johnson DM, Erwin ME (1996) In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones. Antimicrob Agents Chemother 40:720–726

    CAS  Google Scholar 

  191. Barbachyn MR, Brickner SI, Hutchinson DK (1997) Substituted oxazine and thiazine oxazolidinone antimicrobials. Pharmacia & Upjohn Co.: United States US199713

    Google Scholar 

  192. Pfizer, Inc. (2009) A Phase 1, Double-Blind, Randomized, Placebo-Controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of PNU-100480 (PF-02341272) After Administration Of Multiple Escalating Oral Doses To Healthy Adult Subjects. Clinical Trial NCT 0990990 Sponsored by Pfizer. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  193. Pfizer, Inc. (2009) A Phase 1 Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of PNU-100480 (PF-02341272) After First Time Administration Of Ascending Oral Doses To Healthy Adult Subjects Under Fed And Fasted Conditions. Clinical Trial NCT00871949 Sponsored by Pfizer. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  194. Bae SK, Chung WS, Kim EJ, Rhee JK, Kwon JW, Kim WB, Lee MG (2004) Pharmacokinetics of DA-7867, a new oxazolidinone, after intravenous or oral administration to rats: Intestinal first-pass effect. Antimicrob Agents Chemother 48:659–662

    CAS  Google Scholar 

  195. Rudra S, Yadav A, Rao A, Srinivas A, Pandya M, Bhateia P, Mathur T, Malhotra S, Rattan A, Salman M, Mehta A, Cliffe IA, Das B (2007) Synthesis and antibacterial activity of potent heterocyclic oxazolidinones and the identification of RBx 8700. Bioorg Med Chem Lett 17:6714–6719

    CAS  Google Scholar 

  196. Wookey A, Turner PJ, Greenhalgh JM, Eastwood M, Clarke J, Sefton C (2004) AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro. Clin Microbiol Infect 10:247–254

    CAS  Google Scholar 

  197. Meier PA (2009) A Phase-1, Single Center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Safety, Tolerability and Pharmacokinetics (Including Food Effect) of Ascending Oral Doses of AZD5847 in Healthy Male Subjects and Female Subjects of Non-childbearing Potential. Clinical Trial NCT01037725. Sponsored by AstraZeneca. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  198. Shaw A (2010) A Phase I, Single-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD5847 Following Oral Administration to Healthy Male Subjects and Female Subjects of Non-childbearing Potential. Clinical Trial NCT0116258. Sponsored by AstraZeneca. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov

    Google Scholar 

  199. Gregory WA, Brittelli DR, Wang CLJ, Wuonola MA, McRipley RJ, Eustice DC, Eberly VS, Bartholomew PT, Slee AM, Forbes M (1989) Antibacterials – synthesis and structure activity studies of 3-aryl-2-oxooxazolidines.1. The B-group. J Med Chem 32:1673–1681

    CAS  Google Scholar 

  200. Gregory WA, Brittelli DR, Wang CLJ, Kezar HS, Carlson RK, Park CH, Corless PF, Miller SJ, Rajagopalan P, Wuonola MA, McRipley RJ, Eberly VS, Slee AM, Forbes M (1990) Antibacterials – synthesis and structure activity studies of 3-aryl-2-oxooxazolidines. 2. The A group. J Med Chem 33:2569–2578

    CAS  Google Scholar 

  201. Park CH, Brittelli DR, Wang CLJ, Marsh FD, Gregory WA, Wuonola MA, McRipley RJ, Eberly VS, Slee AM, Forbes M (1992) Antibacterials – synthesis and structure activity studies of 3-aryl-2-oxooxazolidines. 4. Multiply-substituted aryl derivatives. J Med Chem 35:1156–1165

    CAS  Google Scholar 

  202. Barbachyn MR, Ford CW (2003) Oxazolidinone structure-activity relationships leading to linezolid. Angew Chem Int Ed 42:2010–2023

    CAS  Google Scholar 

  203. Selvakumar N, Rajulu GG, Reddy KCS, Chary BC, Kumar PK, Madhavi T, Praveena K, Reddy KHP, Takhi M, Mallick A, Amarnath PVS, Kandepu S, Iqbal J (2008) Synthesis, SAR, and antibacterial activity of novel oxazolidinone analogues possessing urea functionality. Bioorg Med Chem Lett 18:856–860

    CAS  Google Scholar 

  204. Alcala L, Ruiz-Serrano MJ, Turegano CPF, Garcia de Viedma D, Diaz-Infantes M, Marin-Arriaza M, Bouza E (2003) In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother 47:416–417

    CAS  Google Scholar 

  205. Rao M, Sood R, Malhotra S, Fatma T, Upadhyay DJ, Rattan A (2006) In vitro bactericidal activity of oxazolidinone, RBx 8700 against Mycobacterium tuberculosis and Mycobacterium avium complex. J Chemother 18:144–150

    CAS  Google Scholar 

  206. Sood R, Rao M, Singhal S, Rattan A (2005) Activity of RBx 7644 and RBx 8700, new investigational oxazolidinones, against Mycobacterium tuberculosis infected murine macrophages. Int J Antimicrob Agents 25:464–468

    CAS  Google Scholar 

  207. Vera-Cabrera L, Gonzalez E, Rendon A, Ocampo-Candiani J, Welsh O, Velazquez-Moreno VM, Choi SH, Molina-Torres C (2006) In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis. Antimicrob Agents Chemother 50:3170–3172

    CAS  Google Scholar 

  208. Lin AH, Murray RW, Vidmar TJ, Marotti KR (1997) The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother 41:2127–2131

    CAS  Google Scholar 

  209. Aoki H, Ke LZ, Poppe SM, Poel TJ, Weaver EA, Gadwood RC, Thomas RC, Shinabarger DL, Ganoza MC (2002) Oxazolidinone antibiotics target the P site on Escherichia coli ribosomes. Antimicrob Agents Chemother 46:1080–1085

    CAS  Google Scholar 

  210. Shinabarger DL, Marotti KR, Murray RW, Lin AH, Melchior EP, Swaney SM, Dunyak DS, Demyan WF, Buysse JM (1997) Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 41:2132–2136

    CAS  Google Scholar 

  211. Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P (2008) The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci USA 105:13339–13344

    CAS  Google Scholar 

  212. Hillemann D, Rusch-Gerdes S, Richter E (2008) In vitro-selected linezolid-resistant Mycobacterium tuberculosis mutants. Antimicrob Agents Chemother 52:800–801

    CAS  Google Scholar 

  213. Richter E, Rusch-Gerdes S, Hillemann D (2007) First linezolid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 51:1534–1536

    CAS  Google Scholar 

  214. Escribano I, Rodriguez C, Llorca B, Garcia-Pachon E, Ruiz M, Royo G (2007) Importance of the efflux pump systems in the resistance of Mycobacterium tuberculosis to Fluoroquinolones and linezolid. Chemotherapy 53:397–401

    CAS  Google Scholar 

  215. Erturan Z, Uzun M (2005) In vitro activity of linezolid against multidrug-resistant Mycobacterium tuberculosis isolates. Int J Antimicrob Agents 26:78–80

    CAS  Google Scholar 

  216. Prammananan T, Chaiprasert A, Leechawengwongs M (2009) In vitro activity of linezolid against multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant (XDR)-TB isolates. Int J Antimicrob Agents 33:190–191

    CAS  Google Scholar 

  217. Schaaf HS, Willemse M, Donald PR (2009) Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis. Pediatr Infect Dis J 28:748–750

    Google Scholar 

  218. von der Lippe B, Sandven P, Brubakk O (2006) Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB) – a report of ten cases. J Infect 52:92–96

    Google Scholar 

  219. Welshman IR, Sisson TA, Jungbluth GL, Stalker DJ, Hopkins NK (2001) Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 22:91–97

    CAS  Google Scholar 

  220. Slatter JG, Stalker DJ, Feenstra KL, Welshman IR, Bruss JB, Sams JP, Johnson MG, Sanders PE, Hauer MJ, Fagerness PE, Stryd RP, Peng GW, Shobe EM (2001) Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of C-14 linezolid to healthy human subjects. Drug Metab Dispos 29:1136–1145

    CAS  Google Scholar 

  221. Metaxas EI, Falagas ME (2009) Update on the safety of linezolid. Expert Opin Drug Saf 8:485–491

    CAS  Google Scholar 

  222. Diaz JCR, Ruiz M, Lopez M, Royo G (2003) Synergic activity of fluoroquinolones and linezolid against Mycobacterium tuberculosis. Int J Antimicrob Agents 21:354–356

    Google Scholar 

  223. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, Kuter DJ (2002) Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 46:2723–2726

    CAS  Google Scholar 

  224. Eker B, Ortmann J, Migliori GB, Sotgiu G, Muetterlein R, Centis R, Hoffmann H, Kirsten D, Schaberg T, Ruesch-Gerdes S, Lange C, German TG (2008) Multidrug- and extensively drug-resistant tuberculosis, Germany. Emerg Infect Dis 14:1700–1706

    Google Scholar 

  225. Lesher GY, Froelich EJ, Gruett MD, Bailey JH, Brundage RP (1962) 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Pharm Chem 91:1063–1065

    CAS  Google Scholar 

  226. Mitscher LA (2005) Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. Chem Rev 105:559–592

    CAS  Google Scholar 

  227. Nakamura S, Nakata K, Katae H, Minami A, Kashimoto S, Yamagishi J, Takase Y, Shimizu M (1983) Activity of AT-2266 compared with those of norfloxacin, pipemidic acid, nalidixic acid, and gentamicin against various experimental infections in mice. Antimicrob Agents Chemother 23:742–749

    CAS  Google Scholar 

  228. Koga H, Itoh A, Murayama S, Suzue S, Irikura T (1980) Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids. J Med Chem 23:1358–1363

    CAS  Google Scholar 

  229. De Souza MV (2005) New fluoroquinolones: a class of potent antibiotics. Mini Rev Med Chem 5:1009–1017

    Google Scholar 

  230. Wise R (1984) Norfloxacin – a review of pharmacology and tissue penetration. J Antimicrob Chemother 13(Suppl B):59–64

    CAS  Google Scholar 

  231. Grohe DK, Zeiler H-j, Metzger KG (1984) 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids, process for their preparation and pharmaceutical compositions containing them. Bayer AG: Germany. EP0049355

    Google Scholar 

  232. Tanaka Y, Hayakawa I, Hiramitsu T (1982) 1,8-cyclic substituted quinoline derivative. Dai Ichi Seiyaku Co Ltd: Japan; JP57203085

    Google Scholar 

  233. Grohe KO, Zeiler H-j, Metzger KG (1991) 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline- and naphthyridine-3-carboxylic acids, processes for their preparation and antibacterial agents containing these compounds. Bayer AG: United States. US5077429

    Google Scholar 

  234. Liu HH (2010) Safety profile of the fluoroquinolones: focus on levofloxacin. Drug Saf 33:353–369

    CAS  Google Scholar 

  235. Mandell L, Tillotson G (2002) Safety of fluoroquinolones: an update. Can J Infect Dis 13:54–61

    CAS  Google Scholar 

  236. Hong CY, Kim YK, Chang JH, Kim SH, Choi H, Nam D, Kwak J-H, Jeong YN, Oh JI, Kim MY (1998) Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof. LG Chemical Ltd, Seoul

    Google Scholar 

  237. Hayakawa IC, Atarashi S, Imamura M, Kimura Y (1994) Spiro compound. Daiichi Seiyaku Co., Ltd, Tokyo

    Google Scholar 

  238. Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, Giordano I, Hann MM, Hennessy A, Hibbs M, Huang J, Jones E, Jones J, Brown KK, Lewis CJ, May EW, Saunders MR, Singh O, Spitzfaden CE, Shen C, Shillings A, Theobald AJ, Wohlkonig A, Pearson ND, Gwynn MN (2010) Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466:935–940

    Google Scholar 

  239. Black MT, Stachyra T, Platel D, Girard AM, Claudon M, Bruneau JM, Miossec C (2008) Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases. Antimicrob Agents Chemother 52:3339–3349

    CAS  Google Scholar 

  240. Gomez L, Hack MD, Wu J, Wiener JJ, Venkatesan H, Santillan A Jr, Pippel DJ, Mani N, Morrow BJ, Motley ST, Shaw KJ, Wolin R, Grice CA, Jones TK (2007) Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis. Bioorg Med Chem Lett 17:2723–2727

    CAS  Google Scholar 

  241. Wiener JJ, Gomez L, Venkatesan H, Santillan A Jr, Allison BD, Schwarz KL, Shinde S, Tang L, Hack MD, Morrow BJ, Motley ST, Goldschmidt RM, Shaw KJ, Jones TK, Grice CA (2007) Tetrahydroindazole inhibitors of bacterial type II topoisomerases. Part 2: SAR development and potency against multidrug-resistant strains. Bioorg Med Chem Lett 17:2718–2722

    CAS  Google Scholar 

  242. Domagala JM (1994) Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother 33:685–706

    CAS  Google Scholar 

  243. Rubinstein E (2001) History of quinolones and their side effects. Chemotherapy 47(Suppl 3):3–8, discussion 44–48

    CAS  Google Scholar 

  244. Gootz TD, Brighty KE (1996) Fluoroquinolone antibacterials: SAR mechanism of action, resistance, and clinical aspects. Med Res Rev 16:433–486

    CAS  Google Scholar 

  245. Bolon MK (2009) The newer fluoroquinolones. Infect Dis Clin North Am 23:1027–1051

    Google Scholar 

  246. Gellert M, O'Dea MH, Itoh T, Tomizawa J (1976) Novobiocin and coumermycin inhibit DNA supercoiling catalyzed by DNA gyrase. Proc Natl Acad Sci USA 73:4474–4478

    CAS  Google Scholar 

  247. Takei M, Fukuda H, Kishii R, Hosaka M (2001) Target preference of 15 quinolones against Staphylococcus aureus, based on antibacterial activities and target inhibition. Antimicrob Agents Chemother 45:3544–3547

    CAS  Google Scholar 

  248. (2008) Moxifloxacin. Tuberculosis (Edinb) 88:127–131

    Google Scholar 

  249. Lougheed KE, Taylor DL, Osborne SA, Bryans JS, Buxton RS (2009) New anti-tuberculosis agents amongst known drugs. Tuberculosis (Edinb) 89:364–370

    CAS  Google Scholar 

  250. Berning SE (2001) The role of fluoroquinolones in tuberculosis today. Drugs 61:9–18

    CAS  Google Scholar 

  251. (2008) Gatifloxacin. Tuberculosis (Edinb) 88:109–111

    Google Scholar 

  252. Wise R, Honeybourne D (1999) Pharmacokinetics and pharmacodynamics of fluoroquinolones in the respiratory tract. Eur Respir J 14:221–229

    CAS  Google Scholar 

  253. (2008) Levofloxacin. Tuberculosis (Edinb) 88:119–121

    Google Scholar 

  254. Lalloo UG, Ambaram A (2010) New antituberculous drugs in development. Curr HIV AIDS Rep 7:143–151

    Google Scholar 

  255. Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X (2010) Global tuberculosis drug development pipeline: the need and the reality. Lancet 375:2100–2109

    Google Scholar 

  256. Alvirez-Freites EJ, Carter JL, Cynamon MH (2002) In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 46:1022–1025

    CAS  Google Scholar 

  257. Poissy J, Aubry A, Fernandez C, Lott MC, Chauffour A, Jarlier V, Farinotti R, Veziris N (2010) Should moxifloxacin be used for the treatment of XDR-TB? An answer from the murine model. Antimicrob Agents Chemother 54(11):4765–4771

    CAS  Google Scholar 

  258. Shandil RK, Jayaram R, Kaur P, Gaonkar S, Suresh BL, Mahesh BN, Jayashree R, Nandi V, Bharath S, Balasubramanian V (2007) Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy. Antimicrob Agents Chemother 51:576–582

    CAS  Google Scholar 

  259. Lienhardt C, Vernon A, Raviglione MC (2010) New drugs and new regimens for the treatment of tuberculosis: review of the drug development pipeline and implications for national programmes. Curr Opin Pulm Med 16:186–193

    CAS  Google Scholar 

  260. Bryskier A, Lowther J (2002) Fluoroquinolones and tuberculosis. Expert Opin Investig Drugs 11:233–258

    CAS  Google Scholar 

  261. Gillespie SH (2009) A randomized placebo-controlled double blind trial comparing 1) a two month intensive phase of ethambutol, moxifloxacin, rifampicin, pyrazinamide versus the standard regimen (two months ethambutol, isoniazid, rifampicin, pyrazinamide followed by four months isoniazid and rifampicin) for the treatment of adults with pulmonary tuberculosis. In: Controlled comparison of treatment shortening regiments in pulmonary tuberculosis (REMoxTB) Clinical Trial NCT 00864383. Sponsored by University College, London. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov.

    Google Scholar 

  262. Lienhardt, C (2005) A randomized open-label controlled trial of a 4-month gatifloxacin-containing regimen versus standard regiment for the treatment of adult patients with pulmonary tuberculosis. Clinical Trial NCT 00216385. Sponsored by Institut de Recherche pour le Developpement. Accessed from National Library of Medicine and National Institutes of Health (US), ClinicalTrials.gov.

    Google Scholar 

  263. Thomas JP, Baughn CO, Wilkinson RG, Shepherd RG (1961) A new synthetic compound with antituberculous activity in mice: ethambutol (dextro-2,2'-(ethylenediimino)-di-l-butanol). Am Rev Respir Dis 83:891–893

    CAS  Google Scholar 

  264. Shepherd RG, Wilkinson RG (1962) Antituberculous agents. II. N, N'-Diisopropylethylenediamine and analogs. J Med Pharm Chem 91:823–835

    CAS  Google Scholar 

  265. Shepherd RG, Baughn C, Cantrall ML, Goodstein B, Thomas JP, Wilkinson RG (1966) Structure-activity studies leading to ethambutol, a new type of antituberculous compound. Ann NY Acad Sci 135:686–710

    CAS  Google Scholar 

  266. Wilkinson RG, Shepherd RG (1969) Compositions and method of treating mycobacterium tuberculosis with 2,2'-(ethylenediimino)-di-1-butanols. American Cyanamid Co: United States, US3463861

    Google Scholar 

  267. Hausler H, Kawakami RP, Mlaker E, Severn WB, Stutz AE (2001) Ethambutol analogues as potential antimycobacterial agents. Bioorg Med Chem Lett 11:1679–1681

    CAS  Google Scholar 

  268. Belanger AE, Besra GS, Ford ME, Mikusova K, Belisle JT, Brennan PJ, Inamine JM (1996) The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol. Proc Natl Acad Sci USA 93:11919–11924

    CAS  Google Scholar 

  269. Telenti A, Philipp WJ, Sreevatsan S, Bernasconi C, Stockbauer KE, Wieles B, Musser JM, Jacobs WR Jr (1997) The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 3:567–570

    CAS  Google Scholar 

  270. Lee RE, Protopopova M, Crooks E, Slayden RA, Terrot M, Barry CE III (2003) Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem 5:172–187

    CAS  Google Scholar 

  271. Protopopova M, Hanrahan C, Nikonenko B, Samala R, Chen P, Gearhart J, Einck L, Nacy CA (2005) Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother 56:968–974

    CAS  Google Scholar 

  272. Boshoff HI, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE III (2004) The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 279:40174–40184

    CAS  Google Scholar 

  273. Jia L, Tomaszewski JE, Hanrahan C, Coward L, Noker P, Gorman G, Nikonenko B, Protopopova M (2005) Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. Br J Pharmacol 144:80–87

    CAS  Google Scholar 

  274. Jia L, Noker PE, Coward L, Gorman GS, Protopopova M, Tomaszewski JE (2006) Interspecies pharmacokinetics and in vitro metabolism of SQ109. Br J Pharmacol 147:476–485

    CAS  Google Scholar 

  275. Jia L, Tomaszewski JE, Noker PE, Gorman GS, Glaze E, Protopopova M (2005) Simultaneous estimation of pharmacokinetic properties in mice of three anti-tubercular ethambutol analogs obtained from combinatorial lead optimization. J Pharm Biomed Anal 37:793–799

    CAS  Google Scholar 

  276. Sun X, Zeckner D, Zhang Y, Sachs RK, Current WL, Rodriguez M, Chen SH (2001) Prodrugs of 3-amido bearing pseudomycin analogues: novel antifungal agents. Bioorg Med Chem Lett 11:1881–1884

    CAS  Google Scholar 

  277. Maryanoff BE, McComsey DF, Costanzo MJ, Yabut SC, Lu T, Player MR, Giardino EC, Damiano BP (2006) Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa. Chem Biol Drug Des 68:29–36

    CAS  Google Scholar 

  278. Burkhart DJ, Barthel BL, Post GC, Kalet BT, Nafie JW, Shoemaker RK, Koch TH (2006) Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases. J Med Chem 49:7002–7012

    CAS  Google Scholar 

  279. Meng Q, Luo H, Liu Y, Li W, Zhang W, Yao Q (2009) Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents. Bioorg Med Chem Lett 19:2808–2810

    CAS  Google Scholar 

  280. (2008) Sq109. Tuberculosis (Edinb) 88:159–161

    Google Scholar 

  281. Protopopova N, Bogatcheva E (2003) Methods of use and compositions for the diagnosis and treatment of infectious disease. Sequella, Inc.: United States. WO2003096987

    Google Scholar 

  282. Makarov V, Riabova OB, Yuschenko A, Urlyapova N, Daudova A, Zipfel PF, Mollmann U (2006) Synthesis and antileprosy activity of some dialkyldithiocarbamates. J Antimicrob Chemother 57:1134–1138

    CAS  Google Scholar 

  283. Makarov V, Manina G, Mikusova K, Mollmann U, Ryabova O, Saint-Joanis B, Dhar N, Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A, Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P, Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V, Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J, Riccardi G, Cole ST (2009) Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324:801–804

    CAS  Google Scholar 

  284. Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC (2005) Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol 187:8020–8025

    CAS  Google Scholar 

  285. Pasca MR, Degiacomi G, Ribeiro AL, Zara F, De Mori P, Heym B, Mirrione M, Brerra R, Pagani L, Pucillo L, Troupioti P, Makarov V, Cole ST, Riccardi G (2010) Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob Agents Chemother 54:1616–1618

    CAS  Google Scholar 

  286. Nikonenko BV, Reddy VM, Protopopova M, Bogatcheva E, Einck L, Nacy CA (2009) Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis. Antimicrob Agents Chemother 53:3138–3139

    CAS  Google Scholar 

  287. Yamaguchi H, Sato S, Yoshida S, Takada K, Itoh M, Seto H, Otake N (1986) Capuramycin, a new nucleoside antibiotic. Taxonomy, fermentation, isolation and characterization. J Antibiot (Tokyo) 39:1047–1053

    CAS  Google Scholar 

  288. Igarashi M, Takahashi Y, Shitara T, Nakamura H, Naganawa H, Miyake T, Akamatsu Y (2005) Caprazamycins, novel lipo-nucleoside antibiotics, from Streptomyces sp. II. Structure elucidation of caprazamycins. J Antibiot (Tokyo) 58:327–337

    CAS  Google Scholar 

  289. Hotoda H, Furukawa M, Daigo M, Murayama K, Kaneko M, Muramatsu Y, Ishii MM, Miyakoshi S, Takatsu T, Inukai M, Kakuta M, Abe T, Harasaki T, Fukuoka T, Utsui Y, Ohya S (2003) Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin. Bioorg Med Chem Lett 13:2829–2832

    CAS  Google Scholar 

  290. Hirano S, Ichikawa S, Matsuda A (2008) Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. Bioorg Med Chem 16:5123–5133

    CAS  Google Scholar 

  291. Koga T, Fukuoka T, Doi N, Harasaki T, Inoue H, Hotoda H, Kakuta M, Muramatsu Y, Yamamura N, Hoshi M, Hirota T (2004) Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo. J Antimicrob Chemother 54:755–760

    CAS  Google Scholar 

  292. Douthwaite S (2001) Structure-activity relationships of ketolides vs. macrolides. Clin Microbiol Infect 7(Suppl 3):11–17

    CAS  Google Scholar 

  293. Zhu ZJ, Krasnykh O, Pan D, Petukhova V, Yu G, Liu Y, Liu H, Hong S, Wang Y, Wan B, Liang W, Franzblau SG (2008) Structure-activity relationships of macrolides against Mycobacterium tuberculosis. Tuberculosis (Edinb) 88(Suppl 1):S49–S63

    CAS  Google Scholar 

  294. Falzari K, Zhu Z, Pan D, Liu H, Hongmanee P, Franzblau SG (2005) In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis. Antimicrob Agents Chemother 49:1447–1454

    CAS  Google Scholar 

  295. Chhabria M, Jani M, Patel S (2009) New frontiers in the therapy of tuberculosis: fighting with the global menace. Mini Rev Med Chem 9:401–430

    CAS  Google Scholar 

  296. Buriankova K, Doucet-Populaire F, Dorson O, Gondran A, Ghnassia J-C, Weiser J, Pernodet J-L (2004) Molecular basis of intrinsic macrolide resistance in the Mycobacterium tuberculosis complex. Antimicrob Agents Chemother 48:143–150

    CAS  Google Scholar 

  297. Fleming A (1929) On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol 10:226–236

    CAS  Google Scholar 

  298. Tipper DJ, Strominger JL (1965) Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine. Proc Natl Acad Sci USA 54:1133–1141

    CAS  Google Scholar 

  299. Hugonnet J-E, Tremblay LW, Boshoff HI, Barry CE III, Blanchard JS (2009) Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 323:1215–1218

    CAS  Google Scholar 

  300. Segura C, Salvado M, Collado I, Chaves J, Coira A (1998) Contribution of beta-lactamases to beta-lactam susceptibilities of susceptible and multidrug-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 42:1524–1526

    CAS  Google Scholar 

  301. Chambers HF, Moreau D, Yajko D, Miick C, Wagner C, Hackbarth C, Kocagoz S, Rosenberg E, Hadley WK, Nikaido H (1995) Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis? Antimicrob Agents Chemother 39:2620–2624

    CAS  Google Scholar 

  302. Gupta R, Lavollay M, Mainardi J-L, Arthur M, Bishai WR, Lamichhane G (2010) The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nat Med 16:466–469

    CAS  Google Scholar 

  303. Chambers HF, Kocagoz T, Sipit T, Turner J, Hopewell PC (1998) Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis 26:874–877

    CAS  Google Scholar 

  304. Holzgrabe U (2009) Meropenem-clavulanate: a new strategy for the treatment of tuberculosis? ChemMedChem 4:1051–1053

    CAS  Google Scholar 

  305. Maruyama T, Yamamoto Y, Kano Y, Kurazono M, Matsuhisa E, Takata H, Takata T, Atsumi K, Iwamatsu K, Shitara E (2007) CP5484, a novel quaternary carbapenem with potent anti-MRSA activity and reduced toxicity. Bioorg Med Chem 15:6379–6387

    CAS  Google Scholar 

  306. Barry VC, Belton JG, Conalty ML, Denneny JM, Edward DW, O'Sullivan JF, Twomey D, Winder F (1957) A new series of phenazines (rimino-compounds) with high antituberculosis activity. Nature 179:1013–1015

    CAS  Google Scholar 

  307. Reddy VM, Nadadhur G, Daneluzzi D, O'Sullivan JF, Gangadharam PR (1996) Antituberculosis activities of clofazimine and its new analogs B4154 and B4157. Antimicrob Agents Chemother 40:633–636

    CAS  Google Scholar 

  308. van Rensburg CE, Joone GK, Sirgel FA, Matlola NM, O'Sullivan JF (2000) In vitro investigation of the antimicrobial activities of novel tetramethylpiperidine-substituted phenazines against Mycobacterium tuberculosis. Chemotherapy 46:43–48

    Google Scholar 

  309. Oliva B, O'Neill AJ, Miller K, Stubbings W, Chopra I (2004) Anti-staphylococcal activity and mode of action of clofazimine. J Antimicrob Chemother 53:435–440

    CAS  Google Scholar 

  310. Cholo MC, Boshoff HI, Steel HC, Cockeran R, Matlola NM, Downing KJ, Mizrahi V, Anderson R (2006) Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis. J Antimicrob Chemother 57:79–84

    CAS  Google Scholar 

  311. Di Santo R, Costi R, Artico M, Massa S, Lampis G, Deidda D, Pompei R (1998) Pyrrolnitrin and related pyrroles endowed with antibacterial activities against Mycobacterium tuberculosis. Bioorg Med Chem Lett 8:2931–2936

    Google Scholar 

  312. Deidda D, Lampis G, Fioravanti R, Biava M, Porretta GC, Zanetti S, Pompei R (1998) Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic Mycobacterium tuberculosis strains. Antimicrob Agents Chemother 42:3035–3037

    CAS  Google Scholar 

  313. Biava M, Cesare Porretta G, Deidda D, Pompei R, Tafi A, Manetti F (2003) Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212. Bioorg Med Chem 11:515–520

    CAS  Google Scholar 

  314. Biava M, Porretta GC, Deidda D, Pompei R, Tafi A, Manetti F (2004) Antimycobacterial compounds. New pyrrole derivatives of BM212. Bioorg Med Chem 12:1453–1458

    CAS  Google Scholar 

  315. Biava M, Porretta GC, Poce G, Deidda D, Pompei R, Tafi A, Manetti F (2005) Antimycobacterial compounds. Optimization of the BM 212 structure, the lead compound for a new pyrrole derivative class. Bioorg Med Chem 13:1221–1230

    CAS  Google Scholar 

  316. Biava M, Porretta GC, Poce G, Supino S, Deidda D, Pompei R, Molicotti P, Manetti F, Botta M (2006) Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity. J Med Chem 49:4946–4952

    CAS  Google Scholar 

  317. Biava M, Porretta GC, Manetti F (2007) New derivatives of BM212: a class of antimycobacterial compounds based on the pyrrole ring as a scaffold. Mini Rev Med Chem 7:65–78

    CAS  Google Scholar 

  318. (2008) LL-3858. Tuberculosis (Edinb) 88:126

    Google Scholar 

  319. Chan DCM, Anderson AC (2006) Towards species-specific antifolates. Curr Med Chem 13:377–398

    CAS  Google Scholar 

  320. Lange RP, Locher HH, Wyss PC, Then RL (2007) The targets of currently used antibacterial agents: lessons for drug discovery. Curr Pharm Des 13:3140–3154

    CAS  Google Scholar 

  321. Suling WJ, Reynolds RC, Barrow EW, Wilson LN, Piper JR, Barrow WW (1998) Susceptibilities of Mycobacterium tuberculosis and Mycobacterium avium complex to lipophilic deazapteridine derivatives, inhibitors of dihydrofolate reductase. J Antimicrob Chemother 42:811–815

    CAS  Google Scholar 

  322. da Cunha EFF, Ramalho TC, de Alencastro RB, Maia ER (2004) Interactions of 5-deazapteridine derivatives with Mycobacterium tuberculosis and with human dihydrofolate reductases. J Biomol Struct Dyn 22:119–130

    Google Scholar 

  323. da Cunha EFF, Ramalho TC, Reynolds RC (2008) Binding mode analysis of 2,4-diamino-5-methyl-5-deaza-6-substituted pteridines with Mycobacterium tuberculosis and human dihydrofolate reductases. J Biomol Struct Dyn 25:377–385

    Google Scholar 

  324. Suling WJ, Seitz LE, Pathak V, Westbrook L, Barrow EW, Zywno-Van-Ginkel S, Reynolds RC, Piper JR, Barrow WW (2000) Antimycobacterial activities of 2,4-diamino-5-deazapteridine derivatives and effects on mycobacterial dihydrofolate reductase. Antimicrob Agents Chemother 44:2784–2793

    CAS  Google Scholar 

  325. El-Hamamsy M, Smith AW, Thompson AS, Threadgill MD (2007) Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis. Bioorg Med Chem 15:4552–4576

    CAS  Google Scholar 

  326. Mahapatra S, Yagi T, Belisle JT, Espinosa BJ, Hill PJ, McNeil MR, Brennan PJ, Crick DC (2005) Mycobacterial lipid II is composed of a complex mixture of modified muramyl and peptide moieties linked to decaprenyl phosphate. J Bacteriol 187:2747–2757

    CAS  Google Scholar 

  327. Lavollay M, Arthur M, Fourgeaud M, Dubost L, Marie A, Veziris N, Blanot D, Gutmann L, Mainardi J-L (2008) The peptidoglycan of stationary-phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation. J Bacteriol 190:4360–4366

    CAS  Google Scholar 

  328. Daffe M, Brennan PJ, McNeil M (1990) Predominant structural features of the cell wall arabinogalactan of Mycobacterium tuberculosis as revealed through characterization of oligoglycosyl alditol fragments by gas chromatography/mass spectrometry and by 1H and 13C NMR analyses. J Biol Chem 265:6734–6743

    CAS  Google Scholar 

  329. McNeil M, Daffe M, Brennan PJ (1990) Evidence for the nature of the link between the arabinogalactan and peptidoglycan of mycobacterial cell walls. J Biol Chem 265:18200–18206

    CAS  Google Scholar 

  330. McNeil M, Daffe M, Brennan PJ (1991) Location of the mycolyl ester substituents in the cell walls of mycobacteria. J Biol Chem 266:13217–13223

    CAS  Google Scholar 

  331. Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64:29–63

    CAS  Google Scholar 

  332. Hui J, Gordon N, Kajioka R (1977) Permeability barrier to rifampin in mycobacteria. Antimicrob Agents Chemother 11:773–779

    CAS  Google Scholar 

  333. Mizuguchi Y, Udou T, Yamada T (1983) Mechanism of antibiotic resistance in Mycobacterium intracellulare. Microbiol Immunol 27:425–431

    CAS  Google Scholar 

  334. David HL, Rastogi N, Clavel-Seres S, Clement F, Thorel MF (1987) Structure of the cell envelope of Mycobacterium avium. Zentralbl Bakteriol Mikrobiol Hyg A 264:49–66

    CAS  Google Scholar 

  335. Rastogi N, Goh KS, David HL (1990) Enhancement of drug susceptibility of Mycobacterium avium by inhibitors of cell envelope synthesis. Antimicrob Agents Chemother 34:759–764

    CAS  Google Scholar 

  336. Draper P (1998) The outer parts of the mycobacterial envelope as permeability barriers. Front Biosci 3:D1253–1261

    CAS  Google Scholar 

  337. Jarlier V, Nikaido H (1990) Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J Bacteriol 172:1418–1423

    CAS  Google Scholar 

  338. Nguyen L, Thompson CJ (2006) Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends Microbiol 14:304–312

    CAS  Google Scholar 

  339. Jarlier V, Nikaido H (1994) Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 123:11–18

    CAS  Google Scholar 

  340. Liu J, Rosenberg EY, Nikaido H (1995) Fluidity of the lipid domain of cell wall from Mycobacterium chelonae. Proc Natl Acad Sci USA 92:11254–11258

    CAS  Google Scholar 

  341. Davis JM, Clay H, Lewis JL, Ghori N, Herbomel P, Ramakrishnan L (2002) Real-time visualization of mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos. Immunity 17:693–702

    CAS  Google Scholar 

  342. Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327:466–469

    CAS  Google Scholar 

  343. Makky K, Duvnjak P, Pramanik K, Ramchandran R, Mayer AN (2008) A whole-animal microplate assay for metabolic rate using zebrafish. J Biomol Screen 13:960–967

    CAS  Google Scholar 

  344. Flynn JL (2006) Lessons from experimental Mycobacterium tuberculosis infections. Microbes Infect 8:1179–1188

    CAS  Google Scholar 

  345. Nuermberger E (2008) Using animal models to develop new treatments for tuberculosis. Semin Respir Crit Care Med 29:542–551

    Google Scholar 

  346. Kramnik I (2008) Genetic dissection of host resistance to Mycobacterium tuberculosis: the sst1 locus and the Ipr1 gene. Curr Top Microbiol Immunol 321:123–148

    CAS  Google Scholar 

  347. Lenaerts AJM, Gruppo V, Brooks JV, Orme IM (2003) Rapid in vivo screening of experimental drugs for tuberculosis using gamma interferon gene-disrupted mice. Antimicrob Agents Chemother 47:783–785

    CAS  Google Scholar 

  348. Gaonkar S, Bharath S, Kumar N, Balasubramanian V, Shandil RK (2010) Aerosol infection model of tuberculosis in wistar rats. Int J Microbiol 2010:426035

    Google Scholar 

  349. McFarland CT, Ly L, Jeevan A, Yamamoto T, Weeks B, Izzo A, McMurray D (2010) BCG vaccination in the cotton rat (Sigmodon hispidus) infected by the pulmonary route with virulent Mycobacterium tuberculosis. Tuberculosis (Edinb) 90:262–267

    CAS  Google Scholar 

  350. McMurray DN (2001) Disease model: pulmonary tuberculosis. Trends Mol Med 7:135–137

    CAS  Google Scholar 

  351. Ordway DJ, Shanley CA, Caraway ML, Orme EA, Bucy DS, Hascall-Dove L, Henao-Tamayo M, Harton MR, Shang S, Ackart D, Kraft SL, Lenaerts AJ, Basaraba RJ, Orme IM (2010) Evaluation of standard chemotherapy in the guinea pig model of tuberculosis. Antimicrob Agents Chemother 54:1820–1833

    CAS  Google Scholar 

  352. Abdul-Majid K-B, Ly LH, Converse PJ, Geiman DE, McMurray DN, Bishai WR (2008) Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice. BMC Microbiol 8:151

    Google Scholar 

  353. Gupta UD, Katoch VM (2009) Animal models of tuberculosis for vaccine development. Indian J Med Res 129:11–18

    CAS  Google Scholar 

  354. Converse PJ, Dannenberg AM Jr, Estep JE, Sugisaki K, Abe Y, Schofield BH, Pitt ML (1996) Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli. Infect Immun 64:4776–4787

    CAS  Google Scholar 

  355. Tsenova L, Sokol K, Freedman VH, Kaplan G (1998) A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death. J Infect Dis 177:1563–1572

    CAS  Google Scholar 

  356. Kolodny NH, Goode ST, Ryan W, Freddo TF (2002) Evaluation of therapeutic effectiveness using MR imaging in a rabbit model of anterior uveitis. Exp Eye Res 74:483–491

    CAS  Google Scholar 

  357. Manabe YC, Dannenberg AM Jr, Tyagi SK, Hatem CL, Yoder M, Woolwine SC, Zook BC, Pitt MLM, Bishai WR (2003) Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis. Infect Immun 71:6004–6011

    CAS  Google Scholar 

  358. Capuano SV III, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, Bissel S, Fuhrman C, Klein E, Flynn JL (2003) Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun 71:5831–5844

    CAS  Google Scholar 

  359. Lin PL, Rodgers M, Smith L, Bigbee M, Myers A, Bigbee C, Chiosea I, Capuano SV, Fuhrman C, Klein E, Flynn JL (2009) Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77:4631–4642

    CAS  Google Scholar 

  360. Sharpe SA, Eschelbach E, Basaraba RJ, Gleeson F, Hall GA, MyIntyre A, Williams A, Kraft SL, Clark S, Gooch K, Hatch G, Orme IM, Marsh PD, Dennis MJ (2009) Determination of lesion volume by MRI and stereology in a macaque model of tuberculosis. Tuberculosis (Edinb) 89:405–416

    CAS  Google Scholar 

  361. Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND, Hagge DA, Khadge S, King M-C, Hawn TR, Moens CB, Ramakrishnan L (2010) The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730

    CAS  Google Scholar 

  362. Scanga CA, Mohan VP, Joseph H, Yu K, Chan J, Flynn JL (1999) Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect Immun 67:4531–4538

    CAS  Google Scholar 

  363. Ilson BE, Jorkasky DK, Curnow RT, Stote RM (1989) Effect of a new synthetic hexapeptide to selectively stimulate growth hormone release in healthy human subjects. J Clin Endocrinol Metab 69:212–214

    CAS  Google Scholar 

  364. Pichugin AV, Yan B-S, Sloutsky A, Kobzik L, Kramnik I (2009) Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol 174:2190–2201

    CAS  Google Scholar 

  365. Miyazaki E, Chaisson RE, Bishai WR (1999) Analysis of rifapentine for preventive therapy in the Cornell mouse model of latent tuberculosis. Antimicrob Agents Chemother 43:2126–2130

    CAS  Google Scholar 

  366. Mitchison DA (2004) The search for new sterilizing anti-tuberculosis drugs. Front Biosci 9:1059–1072

    CAS  Google Scholar 

  367. Nuermberger EL, Yoshimatsu T, Tyagi S, Bishai WR, Grosset JH (2004) Paucibacillary tuberculosis in mice after prior aerosol immunization with Mycobacterium bovis BCG. Infect Immun 72:1065–1071

    CAS  Google Scholar 

  368. Andries K, Gevers T, Lounis N (2010) Bactericidal potencies of new regimens are not predictive for their sterilizing potencies in a murine model of tuberculosis. Antimicrob Agents Chemother 54(11):4540–4544

    CAS  Google Scholar 

  369. Ahmad Z, Nuermberger EL, Tasneen R, Pinn ML, Williams KN, Peloquin CA, Grosset JH, Karakousis PC (2010) Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig. J Antimicrob Chemother 65:729–734

    CAS  Google Scholar 

  370. Rosenthal IM, Zhang M, Almeida D, Grosset JH, Nuermberger EL (2008) Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis? Am J Respir Crit Care Med 178:989–993

    CAS  Google Scholar 

  371. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, Gordin F, Horsburgh CR, Horton J, Khan A, Lahart C, Metchock B, Pachucki C, Stanton L, Vernon A, Villarino ME, Wang YC, Weiner M, Weis S, Tuberculosis Trials C (2002) Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 360:528–534

    Google Scholar 

  372. Mitchison DA, Chang KC (2009) Experimental models of tuberculosis: can we trust the mouse? Am J Respir Crit Care Med 180:201–202

    Google Scholar 

  373. Emori M, Saito H, Sato K, Tomioka H, Setogawa T, Hidaka T (1993) Therapeutic efficacy of the benzoxazinorifamycin KRM-1648 against experimental Mycobacterium avium infection induced in rabbits. Antimicrob Agents Chemother 37:722–728

    CAS  Google Scholar 

  374. Dorman SE, Hatem CL, Tyagi S, Aird K, Lopez-Molina J, Pitt MLM, Zook BC, Dannenberg AM Jr, Bishai WR, Manabe YC (2004) Susceptibility to tuberculosis: clues from studies with inbred and outbred New Zealand White rabbits. Infect Immun 72:1700–1705

    CAS  Google Scholar 

  375. Tsenova L, Mangaliso B, Muller G, Chen Y, Freedman VH, Stirling D, Kaplan G (2002) Use of IMiD3, a thalidomide analog, as an adjunct to therapy for experimental tuberculous meningitis. Antimicrob Agents Chemother 46:1887–1895

    CAS  Google Scholar 

  376. Kailasam S, Daneluzzi D, Gangadharam PR (1994) Maintenance of therapeutically active levels of isoniazid for prolonged periods in rabbits after a single implant of biodegradable polymer. Tuber Lung Dis 75:361–365

    CAS  Google Scholar 

  377. Manabe YC, Kesavan AK, Lopez-Molina J, Hatem CL, Brooks M, Fujiwara R, Hochstein K, Pitt MLM, Tufariello J, Chan J, McMurray DN, Bishai WR, Dannenberg AM Jr, Mendez S (2008) The aerosol rabbit model of TB latency, reactivation and immune reconstitution inflammatory syndrome. Tuberculosis (Edinb) 88:187–196

    CAS  Google Scholar 

  378. Flynn JL, Capuano SV, Croix D, Pawar S, Myers A, Zinovik A, Klein E (2003) Non-human primates: a model for tuberculosis research. Tuberculosis (Edinb) 83:116–118

    CAS  Google Scholar 

  379. Pecherstorfer M, Thiebaud D (1992) Treatment of resistant tumor-induced hypercalcemia with escalating doses of pamidronate (APD). Ann Oncol 3:661–663

    CAS  Google Scholar 

  380. Langermans JAM, Doherty TM, Vervenne RAW, van der Laan T, Lyashchenko K, Greenwald R, Agger EM, Aagaard C, Weiler H, van Soolingen D, Dalemans W, Thomas AW, Andersen P (2005) Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 23:2740–2750

    CAS  Google Scholar 

  381. Zaleskis R (2006) Adverse effects of anti-tuberculosis chemotherapy. Eur Resp Dis:47–49

    Google Scholar 

  382. Craig WA (2003) Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 17:479–501

    Google Scholar 

  383. Andes D, Craig WA (2002) Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 19:261–268

    CAS  Google Scholar 

  384. Barroso EC, Pinheiro VGF, Facanha MC, Carvalho MRD, Moura ME, Campelo CL, Peloquin CA, Guerrant RL, Lima AAM (2009) Serum concentrations of rifampin, isoniazid, and intestinal absorption, permeability in patients with multidrug resistant tuberculosis. Am J Trop Med Hyg 81:322–329

    CAS  Google Scholar 

  385. Davies GR, Nuermberger EL (2008) Pharmacokinetics and pharmacodynamics in the development of anti-tuberculosis drugs. Tuberculosis (Edinb) 88(Suppl 1):S65–S74

    CAS  Google Scholar 

  386. Jayaram R, Shandil RK, Gaonkar S, Kaur P, Suresh BL, Mahesh BN, Jayashree R, Nandi V, Bharath S, Kantharaj E, Balasubramanian V (2004) Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother 48:2951–2957

    CAS  Google Scholar 

  387. Jayaram R, Gaonkar S, Kaur P, Suresh BL, Mahesh BN, Jayashree R, Nandi V, Bharat S, Shandil RK, Kantharaj E, Balasubramanian V (2003) Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother 47:2118–2124

    CAS  Google Scholar 

  388. Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL (2004) Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. J Infect Dis 190:1642–1651

    CAS  Google Scholar 

  389. Conde MB, Efron A, Loredo C, De Souza GRM, Graca NP, Cezar MC, Ram M, Chaudhary MA, Bishai WR, Kritski AL, Chaisson RE (2009) Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 373:1183–1189

    CAS  Google Scholar 

  390. Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, Heilig CM, Bernardo J, Choudhri S, Grosset JH, Guy E, Guyadeen P, Leus MC, Maltas G, Menzies D, Nuermberger EL, Villarino M, Vernon A, Chaisson RE, Tuberculosis Trials C (2009) Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 180:273–280

    CAS  Google Scholar 

  391. Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff SS, Zhao Z, Vernon A, Chaisson RE (2006) Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 174:331–338

    CAS  Google Scholar 

  392. Johnson JL, Hadad DJ, Dietze R, Maciel ELN, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH (2009) Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med 180:558–563

    Google Scholar 

  393. Li L, Mahan CS, Palaci M, Horter L, Loeffelholz L, Johnson JL, Dietze R, Debanne SM, Joloba ML, Okwera A, Boom WH, Eisenach KD (2010) Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy. J Clin Microbiol 48:46–51

    CAS  Google Scholar 

  394. Wallis RS, Pai M, Menzies D, Doherty TM, Walzl G, Perkins MD, Zumla A (2010) Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice. Lancet 375:1920–1937

    CAS  Google Scholar 

  395. Cannas A, Goletti D, Girardi E, Chiacchio T, Calvo L, Cuzzi G, Piacentini M, Melkonyan H, Umansky SR, Lauria FN, Ippolito G, Tomei LD (2008) Mycobacterium tuberculosis DNA detection in soluble fraction of urine from pulmonary tuberculosis patients. Int J Tuberc Lung Dis 12:146–151

    CAS  Google Scholar 

  396. Reither K, Saathoff E, Jung J, Minja LT, Kroidl I, Saad E, Huggett JF, Ntinginya EN, Maganga L, Maboko L, Hoelscher M (2009) Low sensitivity of a urine LAM-ELISA in the diagnosis of pulmonary tuberculosis. BMC Infect Dis 9:141

    Google Scholar 

  397. Tessema TA, Bjune G, Assefa G, Svenson S, Hamasur B, Bjorvatn B (2002) Clinical and radiological features in relation to urinary excretion of lipoarabinomannan in Ethiopian tuberculosis patients. Scand J Infect Dis 34:167–171

    CAS  Google Scholar 

  398. Phillips M, Cataneo RN, Condos R, Ring Erickson GA, Greenberg J, La Bombardi V, Munawar MI, Tietje O (2007) Volatile biomarkers of pulmonary tuberculosis in the breath. Tuberculosis (Edinb) 87:44–52

    CAS  Google Scholar 

  399. Carrara S, Vincenti D, Petrosillo N, Amicosante M, Girardi E, Goletti D (2004) Use of a T cell-based assay for monitoring efficacy of antituberculosis therapy. Clin Infect Dis 38:754–756

    CAS  Google Scholar 

  400. Wassie L, Demissie A, Aseffa A, Abebe M, Yamuah L, Tilahun H, Petros B, Rook G, Zumla A, Andersen P, Doherty TM, Group VS (2008) Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time. PLoS ONE 3:e1522

    Google Scholar 

  401. Turgut T, Akbulut H, Deveci F, Kacar C, Muz MH (2006) Serum interleukin-2 and neopterin levels as useful markers for treatment of active pulmonary tuberculosis. Tohoku J Exp Med 209:321–328

    CAS  Google Scholar 

  402. Baylan O, Balkan A, Inal A, Kisa O, Albay A, Doganci L, Acikel CH (2006) The predictive value of serum procalcitonin levels in adult patients with active pulmonary tuberculosis. Jpn J Infect Dis 59:164–167

    CAS  Google Scholar 

  403. Hosp M, Elliott AM, Raynes JG, Mwinga AG, Luo N, Zangerle R, Pobee JO, Wachter H, Dierich MP, McAdam KP, Fuchs D (1997) Neopterin, beta 2-microglobulin, and acute phase proteins in HIV-1-seropositive and -seronegative Zambian patients with tuberculosis. Lung 175:265–275

    CAS  Google Scholar 

  404. Lee H-M, Shin JW, Kim JY, Park IW, Choi BW, Choi JC, Seo JS, Kim CW (2010) HRCT and whole-blood interferon-gamma assay for the rapid diagnosis of smear-negative pulmonary tuberculosis. Respiration 79:454–460

    CAS  Google Scholar 

  405. Lee SW, Jang YS, Park CM, Kang HY, Koh W-J, Yim J-J, Jeon K (2010) The role of chest CT scanning in TB outbreak investigation. Chest 137:1057–1064

    Google Scholar 

  406. Wang YH, Lin AS, Lai YF, Chao TY, Liu JW, Ko SF (2003) The high value of high-resolution computed tomography in predicting the activity of pulmonary tuberculosis. Int J Tuberc Lung Dis 7:563–568

    CAS  Google Scholar 

  407. Demura Y, Tsuchida T, Uesaka D, Umeda Y, Morikawa M, Ameshima S, Ishizaki T, Fujibayashi Y, Okazawa H (2009) Usefulness of 18F-fluorodeoxyglucose positron emission tomography for diagnosing disease activity and monitoring therapeutic response in patients with pulmonary mycobacteriosis. Eur J Nucl Med Mol Imaging 36:632–639

    Google Scholar 

  408. Sirgel FA, Fourie PB, Donald PR, Padayatchi N, Rustomjee R, Levin J, Roscigno G, Norman J, McIlleron H, Mitchison DA (2005) The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med 172:128–135

    Google Scholar 

  409. Jindani A, Dore CJ, Mitchison DA (2003) Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days. Am J Respir Crit Care Med 167:1348–1354

    Google Scholar 

  410. Ehrt S, Schnappinger D (2006) Controlling gene expression in mycobacteria. Future Microbiol 1:177–184

    CAS  Google Scholar 

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  1. Tuberculosis Research Section, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, USA

    Gwendolyn A. Marriner, Amit Nayyar, Eugene Uh, Sharon Y. Wong, Tathagata Mukherjee, Laura E. Via, Matthew Carroll, Rachel L. Edwards, Todd D. Gruber, Inhee Choi, Jinwoo Lee, Kriti Arora, Kathleen D. England, Helena I. M. Boshoff & Clifton E. Barry III

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Marriner, G.A. et al. (2011). The Medicinal Chemistry of Tuberculosis Chemotherapy. In: Elliott, R. (eds) Third World Diseases. Topics in Medicinal Chemistry, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2011_13

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