We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Published Online:https://doi.org/10.4155/ppa.15.9

Tuberculosis caused by Mycobacterium tuberculosis is a global health emergency. This deadly disease has far-reaching social and economic implications. Diseased individuals need prolonged polypharmacy which is not without ill effects. Treatment compliance is often compromised contributing to rising resistance. HIV co-infection has further worsened the scenario. On the other hand, no new anti-TB drug has hit the market in last 4–5 decades. After a long latency, only the last few years have witnessed growing research in this direction and a widening anti-TB drug clinical pipeline. The compounds in preclinical stage of development have also shown a heartening increase. The present review is an attempt to discuss novel promising patents in this field.

Papers of special note have been highlighted as: • of interest

References

  • 1 Keshavjee S, Farmer PE. 200th anniversary article: tuberculosis, drug resistance and the history of modern medicine. N. Engl. J. Med. 367, 931–936 (2012).
  • 2 Zumla A, Raviglione M, Hafner R, Fordham von Reyn C. Current concepts: tuberculosis. N. Engl. J. Med. 368, 745–755 (2013).
  • 3 World Health Organization. WHO Report 2014: Global Tuberculosis Control. WHO/HTM/TB/2014.19. www.who.int/tb/publications/global_report/en/.
  • 4 van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE. New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development. Antimicrob. Agents Chemother. 53(3), 849–862 (2009).• Detailed discussion on some new antituberculosis agents
  • 5 Dasgupta SB, Pieters J. Striking the right balance determines TB or not TB. Front. Immunol. 5, 455–463 (2014).• Vivid description of the pathogenesis, virulence factors and host immunity.
  • 6 Rhee KY, de Carvalho LPS, Bryk R et al. Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier. Trends Microbiol. 19(7), 307–314 (2011).
  • 7 Griffin JE, Pandey AK, Gilmore SA et al. Cholesterol metabolism in Mycobacterium tuberculosis requires transcriptional and metabolic adaptations. Chem. Biol. 19(2), 218–227 (2012).
  • 8 Butov DO, Yanovsky FG, Kuzhko MM et al. Dynamics of oxidant-antioxidant system in patients with multidrug-resistant tuberculosis receiving anti-mycobacterial therapy. J. Pulm. Respir. Med. 3(5), 161 (2013).
  • 9 Bharati BK, Chatterji D. Quorum sensing and pathogenesis: role of small signalling molecules in bacterial persistence. Curr. Sci. 105(5), 643–656 (2013).
  • 10 Kumar R. Glyoxylate shunt: combating mycobacteria at forefront. Int. J. Integr. Biol. 7(2), 69–72 (2009).
  • 11 Jozefowski S, Sobota A, Kwiatkowska K. How Mycobacterium tuberculosis subverts host immune responses. BioEssays 30, 943–954 (2008).
  • 12 Elkington PT, Ugrate-Gil CA, Friedland JS. Matrix metalloproteinases in tuberculosis. Eur. Respir. J. 38(2), 456–464 (2011).
  • 13 Lienhardt C, Raviglione M, Spigelman M et al. New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future. J. Infect. Dis. 205(S2), S241–249 (2012).• Elaborate description about novel antimycobacterial drugs and their future.
  • 14 Tam C-M, Yew WW, Yuen K-Y. Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects. Expert Rev. Clin. Pharmacol. 2(4), 405–421 (2009).
  • 15 Sarkar S, Mavanur RS. An overview of tuberculosis chemotherapy-a literature review. J. Pharm. Pharm. Sci. 14(2), 148–161 (2011).
  • 16 Kaur M, Garg T, Rath G, Goyal AK. Current nanotechnological strategies for effective delivery of bioactive drug molecules in the treatment of tuberculosis. Crit. Rev. Ther. Drug Carrier Syst. 31(1), 49–88 (2014).
  • 17 Tomioka H. Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship. Curr. Pharm. Des. 20(27), 4305–4306 (2014).
  • 18 Ganihigama DU et al. Antimycobacterial activity of natural products and synthetic agents: pyrroloquinolines and vermelhotin as anti-tubercular leads against clinical multidrug resistant isolates of Mycobacterium tuberculosis. Eur. J. Med. Chem. 89, 1–12 (2015).
  • 19 Lai HM, Mazlan NA, Yusoff MS, Harun SN, Wee LJ, Thambrin MF. Management of side effects and drug interactions of anti-mycobacterial in tuberculosis. WebmedCentral INFECTIOUS DISEASES 2(12), WMC002749 (2011).
  • 20 Vora C, Patadia R, Mittal K, Mashru R. Recent patents and advances on anti-tuberculosis drug delivery and formulations. Recent Pat. Drug Deliv. Formul. 20137(2), 138–149 (2013).• Detailed account about newer drug delivery technologies and their application to tuberculosis.
  • 21 Limonov VL. WO2154077 (2012).
  • 22 du Toit LC, Danckwerts MP, Pillay V, Cooppan S, Choonara YE. US0179170 (2010).
  • 23 Noa Sic Aps: US8623864 (2014).
  • 24 Simons SO, Kristiansen JE, Hajos G et al. Activity of the efflux pump inhibitor SILA 421 against drug-resistant tuberculosis. Int. J. Antimicrob. Agents 41(5), 488–489 (2013).
  • 25 Adams KN, Szumowski JD, Ramakrishnan L. Verapamil and its metabolite norverapamil inhibit macrophage-induced, bacterial efflux-pump-mediated tolerance to multiple anti-tubercular drugs. J. Infect. Dis. 210(3), 456–466 (2014).
  • 26 Placido R, Auricchio G, Falzoni S et al. P2X(7) purinergic receptors and extracellular ATP mediated apoptosis of human monocytes/macrophages infected with Mycobacterium tuberculosis reducing the intracellular bacterial viability. Cell. Immunol. 244(1), 10–18 (2006).
  • 27 Parabolic Biologicals SPRL: WO1160684 (2011).
  • 28 US Department of Health and Human Services: WO3019926 (2013).
  • 29 The International Centre for Diarrhoeal Disease Research: WO2140504 (2012).
  • 30 Summit Corp Plc.: WO8009894 (2008).
  • 31 Hemphill TA. The NIH promotes drug repurposing and rescue. Research-Technology Management 55(5), September/October (2012).
  • 32 Diacon AH et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 380(9846), 986–993 (2012).
  • 33 Lee M, Lee J, Carroll MW et al. Linezolid for treatment of chronic extensively drug resistant tuberculosis. N. Engl. J. Med. 367, 1508–1518 (2012).
  • 34 van Ingen J. The broad-spectrum antimycobacterial activities of phenothiazines, In vitro: somewhere in all of this there may be patentable potentials. Recent Pat Antiinfect Drug Discov 6(2), 104–109 (2011).
  • 35 Bkg Pharma Aps. US0066451 (2014).
  • 36 The Trustees of Columbia University in the city of New York: US0199289 (2014).
  • 37 Horita Y, Takii T, Yagi T et al. Anti-tubercular activity of Disulfiram, an anti-alcoholism drug, against multi-drug and extensively drug-resistant Mycobacterium tuberculosis isolates. Antimicrob. Agents Chemother. 56(8), 4140–4145 (2012).
  • 38 Cornell Research Foundation Inc. US0118274 (2011).
  • 39 Kazakhstan Enterprises Research Centre: WO2091534 (2012).
  • 40 Nabriva Theraprutics Ag. US8088823 (2012).
  • 41 Activbiotics Pharma Llc. WO2103119 (2012).
  • 42 Activbiotics Pharma Llc. WO2203116 (2012).
  • 43 Rychtarčíková Z, Krátký M, Gazvoda M et al. N-substituted 2-isonicotinoylhydrazinecarboxamides-new antimycobacterial active molecules. Molecules 19, 3851–3868 (2014).
  • 44 Campos MM. Preclinical evaluation of novel anti-tuberculosis molecules. BMC Proc. 8(Suppl 4), O17 (2014).
  • 45 Sequella Inc. US US7884097 (2011).
  • 46 Shirude PS, Madhavapeddi P, Tucker JA et al. Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium Tuberculosis. ACS Chem. Biol. 8(3), 519–523 (2013).
  • 47 Lu Y, Zheng M, Wang B et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation Antimicrob. Agents Chemother. 55(11), 5185–5193 (2011).
  • 48 Institute Materia Medica/Beijing Tuberculosis and Thoracic Tumor Research Institute. US0243327 (2014).
  • 49 Kamal A, Azeeza S, Malik MS, Shaik AA, Rao MV. Efforts towards the development of new antitubercular agents: potential for thiolactomycin based compounds. J. Pharm. Pharm. Sci. 11(2), 56s–80s (2008).• Discussion about current and newer anti-TB drugs and detailed narration on thiolactomycin and its derivatives.
  • 50 Gler MT, Skripconoka V, Sanchez-Garavito E et al. Delamanid for multi drug resistant pulmonary tuberculosis N Engl J Med 366, 2151–2160 (2012).
  • 51 Rawat B, Rawat DS. Antituberculosis drug research: a critical overview. Med. Res. Rev. 33, 693–764 (2013).
  • 52 Janssen Pharmaceutica N.V. US7498343 (2009).
  • 53 Lechartier B, Rybniker J, Zumla A, Cole ST. Tuberculosis drug discovery in the post-post genomic era. EMBO Mol. Med. 6(2): 158–168 (2014).• Special notes on new antimycobacterial molecules and drug targets.
  • 54 Lupin Limited: US7691837 (2010).
  • 55 Astrazeneca Ab: US2035219 (2012).
  • 56 Molina-Torres CA, Barba-Marines A, Valles-Guerra O et al. Intracellular activity of tedizolid phosphate and ACH-702 versus Mycobacterium tuberculosis infected macrophages. Annals of Clinical Mircobiology and Antimicrobials 13(1), 13–17 (2014).
  • 57 Trius Therapeutics Inc. US0102523 (2013).
  • 58 Ranbaxy Lab Ltd. WO6043121 (2006).
  • 59 Lupin Limited. US7691889 (2010).
  • 60 Joint Stock Company ‘Pharmasyntez’. US0052265 (2013).
  • 61 ETH Zurich. WO4040709 (2014).
  • 62 Meiji Seika Kaisha Ltd, Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai. US0005371 (2014).
  • 63 Sequella Inc. US0281054 (2009).
  • 64 Siricilla S, Mitachi K, Wan B, Franzblau SG, Kurosu M. Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. J. Antibiot. (Tokyo) doi:10.1038/ja.2014.133 (2014) (Epub ahead of print).
  • 65 Daiichi Sankyo Company Limited US8476429 (2013).
  • 66 Achillon Pharmaceuticals Inc. US0114601 (2012).
  • 67 Briguglio I, Piras S, Corona P, Antonietta Pirisi M, Jabes D, Carta A. SAR and anti-mycobacterial activity of quinolones and triazoloquinolones: an update. Anti-Infect. Agents 11(1), 75–89 (2013).
  • 68 Garg HK, Shrivastava A. Evaluation and impact of anti-tuberculosis drug: a review. Int. J. Sci. Res. 2(7), doi:10.15373/22778179/July2013/8 (2013).
  • 69 University of Tennessee Research Foundation. US0249155 (2014).
  • 70 B & C Biopharm.: WO2144790 (2012).
  • 71 Ocean university of China. CN102603525 (2012).
  • 72 Council of Scientific and Industrial Research. US8865910 (2012).
  • 73 University of Virginia Patent Foundation. US0317070 (2013).
  • 74 Indian Council of Scientific and Industrial Research. WO2164572 (2012).
  • 75 Jenrin Discovery. WO2068560 (2012).
  • 76 Sequella Inc.: US8198303 (2012).
  • 77 Pethe K, Bifani P, Jang J et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med. 19(9), 1157–1160 (2013).
  • 78 The Research Foundation of State University of New York. US8232410 (2012).
  • 79 Meyyanathan SN. IP254676 (2012).
  • 80 Universidade Estadual Paulista Julio De Mesquita Filho-UNESP. WO1137503 (2011).
  • 81 Unither Virology, Llc. WO4143999 (2014).
  • 82 Universiteit Utrecht Holding B.V., Stichting Voor De Technische Wetenschappen. WO4017915 (2014).
  • 83 GlaxoSmithKline. US0288133 (2014).
  • 84 Glaxo Group Limited. US0203802 (2013).
  • 85 Glaxo Group Limited. US0095064 (2012).
  • 86 Agency for Science, Technology and Research, Singapore Health Services Pte Ltd.: WO3036207 (2013).
  • 87 The Broad Institute Inc. and Massachusetts General Hospital. WO3049567 (2013).
  • 88 Vertex Pharmaceuticals Incorporated. WO1019405 (2011).
  • 89 Klein LL, Petukhova V, Wan B et al. A novel indigoid anti-tuberculosis agent. Bioorg. Med. Chem. Lett. 24(1), 268–270 (2014).
  • 90 Sanofi US0245008 (2013).
  • 91 Sichuan University. WO2162912 (2012).
  • 92 Lilienkampf A, Pieroni M, Franzblau SG, Bishai WR, Kozikowski AP. Derivatives of 3-isoxazolecarboxylic acid esters: a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis. Curr. Top. Med. Chem. 12, 729–734 (2012).
  • 93 Onajole OK, Govender K, Govender P et al. Pentacyclo-undecane derived cyclic tetra-amines: synthesis and evaluation as potent anti-tuberculosis agents. Eur. J. Med. Chem. 44(11), 4297–4305 (2009).
  • 94 The Regents of the University of Colorado. EP2520654 (2012).
  • 95 Cornell University. US0190234 (2011).
  • 96 President and Fellows of Harvard College. US0243255 (2014).
  • 97 Hodges RS, Ziqing J. US0099614 (2010).
  • 98 Khara JS, Wang Y, Ke XY et al. Anti-mycobacterial activities of synthetic cationic α-helical peptides and their synergism with rifampicin. Biomaterials 35(6), 2032–2038 (2014).
  • 99 Forchungzentrum Borstel, Christian-Albrechts-Universitat Zu Kiel. WO1047814 (2011).
  • 100 Cumbre Pharmaceuticals Inc. US0143373 (2009).
  • 101 University of Georgia Research Foundation Inc. WO3148174 (2013).
  • 102 Sachdeva P, Misra R, Tyagi AK, Singh Y. The sigma factors of Mycobacterium tuberculosis: regulation of the regulators. FEBS J. 277(3), 605–626 (2010).
  • 103 Ryndak M, Wang S, Smith I. PhoP, a key player in Mycobacterium tuberculosis virulence. Trends Microbiol. 16, 528–534 (2008).
  • 104 Leblanc C, Prudhomme T, Tabouret G et al. 4′-phosphopantetheinyl transferase PptT, a new drug target required for Mycobacterium tuberculosis growth and persistence in vivo. PLoS Pathog. 8(12), e1003097 (2012).
  • 105 GlaxoSmithKline. WO2143522 (2012).
  • 106 Novartis Ag. WO4037900 (2014).
  • 107 Grzegorzewicz AE, Pham H, Gundi VA et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat. Chem. Biol. 8, 334–341 (2012).
  • 108 Arvind A, Kumar V, Saravanan P, Mohan CG. Homology modelling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis. Interdiscip. Sci. 4(3), 223–238 (2012).
  • 109 Leibniz Inst Naturstoff Forsch. US0286130 (2010).
  • 110 Ecole Polytechnique Federale de Lausanne (Epfl). WO0245007 (2013).
  • 111 Chatterji M, Shandil R, Manjunatha MR et al. 1,4-azaindole, a potential drug candidate for treatment of tuberculosis. Antimicrob. Agents Chemother. 58(9), 5325–5331 (2014).
  • 112 Panda M, Ramachandran S, Ramachandran V et al. Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity. J. Med. Chem. 57(11), 4761–4771 (2014).
  • 113 Mann FM, Xu M, Deavenport EK, Peters RJ. Functional characterization and evolution of the isotuberculosinol operon in mycobacterium tuberculosis and related mycobacteria. Front. Microbiol. 3, 368 (2012).
  • 114 Huang X, Huang H, Li H et al. Asperterpenoid A, a new sesterterpenoid as an inhibitor of Mycobacterium tuberculosis protein tyrosine phosphatase B from the culture of Aspergillus sp. 16–5c. Org. Lett. 15(4), 721–723 (2013).
  • 115 Mckenny ES, Sargent M, Khan H et al. Lipophilic prodrugs of FR900098 are antimicrobial against Francisella novicida in vivo and in vitro and show GlpT independent efficacy. PLoS ONE 7(10), E38167 (2012).
  • 116 George Washington University et al: WO3006444 (2013).
  • 117 Smith JM, Warringtom NV, Vierling RJ et al. Targeting DXP synthase in human pathogens: enzyme inhibition and antimicrobial activity of butylacetylphosphonate. J. Antibiot. 67, 77–83 (2014).
  • 118 Indiana University Research and Technology Corporation. WO2149049 (2012).
  • 119 FASgen Inc., The John Hopkins University. US0135568 (2006).
  • 120 Cornell Research Foundation Inc., Sloan-Kettering Institute for Cancer Research. US0024611 (2014).
  • 121 University of Notre Dame Du Lac. US6310058 (2001).
  • 122 The Texas A and M university system. US8664255 (2014).
  • 123 Lucile WE, Reynolds RC, Suling WJ. US0113429 (2010).
  • 124 University of Pittsburgh of the Commonwealth system of Higher Education. US0331460 (2013).
  • 125 Gilead Sciences Inc. US7427624 (2008).
  • 126 Uti Limuted Partnership. US0070860 (2008).
  • 127 Hawn TR, Matheson AI, Maley SN, Vandal O. Host-directed therapeutics for Tuberculosis: can we harness the host? Microbiol. Mol. Biol. Rev. 77(4), 4608–4627 (2013).
  • 128 van der Vaart M, Korbee CJ, Lamers GE et al. The DNA damage-regulated autophagy modulator DRAM1 links mycobacterial recognition via TLP-MYD88 to autophagic defense. Cell host microbe 15(6), 753–767 (2014).
  • 129 University of Pittsburgh of the Commonwealth system of Higher Education: WO3134416 (2013).
  • 130 Stanley SA, Barczak AK, Silvis MR et al. Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth. PLoS Pathog. 10(2): e1003946 (2014).
  • 131 Avi Biopharma. WO2064991 (2012).
  • 132 Rath M. WO2177520 (2012).
  • 133 Orme IM. Vaccine development for tuberculosis: current progress. Drugs 73, 1015–1024 (2013).
  • 134 The Regents of the University of California. US8163294 (2012).
  • 135 Universidade Federal de Minas Gerais. WO2088577 (2012).
  • 136 Isis Innovation Limited. WO2052748 (2012).
  • 137 Uab Research Foundation. WO3033363 (2013).
  • 138 King's College of London, St. George's University of London, University of Dundee. WO2076868 (2012).
  • 139 University of Central Florida Research Foundation Inc. EP2771469 (2013).
  • 140 Panseeta P, Lomchoey K, Prabpai S et al. Antiplasmodial and antimycobacterial cyclopeptide alkaloids from the root of Ziziphus mauritiana. Phytochemistry 72(9), 909–915 (2011).
  • 141 Billings Pharmaceuticals Inc. US7321002 (2008).
  • 142 Samad A, Sultana Y, Akhter MS, Aqil M. Treatment of tuberculosis: use of active pharmaceuticals. Recent Pat. Antiinfect. Drug Discov. 3(1), 34–44 (2008).
  • 143 Council of Scientific and Industrial Research. US0171498 (2014).
  • 144 Martins D, Carrion LL, Ramos DF et al. Anti-tuberculosis activity of oleanolic acid and ursolic acid isolated from the dichlormethane extract of leaves from Duroia macrophylla. BMC Proc. 8(Suppl. 4), P3 (2014).
  • 145 Mann A, Ibrahim K, Oyewale AO, Amupitan JO, Fatope MO, Okogun JL. Antimycobacterial Friedelane-terpenoid from the root bark of Terminalia Avicennioides. Am. J. Chem. 1(2), 52–55 (2011).
  • 146 Council of Scientific and Industrial Research. US0040007 (2013).
  • 147 Yale University. US0101688 (2013).