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Urgency of novel anti-tuberculosis strategies: a prospective challenge

Kausar Malik, Aleem Razzaq, Hafiz Ghufran, Muhammad Abid Naseer, Yahya Tariq, Zaheer Abbas, Muhammad Hamza Basit, Arshia Nazir, Adeena Saeed, Rashid Bhatti, Muhammad Shahid, Areeba Fatima, Haleema Sadia

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Int. J. Biosci.15(2), 281-296, August 2019

DOI: http://dx.doi.org/10.12692/ijb/15.2.281-296


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Tuberculosis (TB) is a fatal infectious disease, caused by bacterium called Mycobacterium tuberculosis, killing nearly two million people every year. The increasing incidence of resistance of Mycobacterium tuberculosis strains to currently used drugs due to inadequate dosing and incomplete treatment regimens is a major factor contributing to the current TB epidemic. Due to this concern, scientists have renovated their approaches to the finding of novel anti-tuberculous drugs and the development of the nanoparticle-based delivery system to subdue technological drawbacks and improve the effectiveness of therapeutic drugs. This article deals with the following areas: first, the present status of the development of new anti-tuberculous drugs is reviewed. This includes the newly approved drugs bedaquiline and delaminid, and other new promising anti-tuberculous agents, such asnitroimidazoles, diarylquinolines and oxazolidinones; and second, the development of new nanotechnology-based therapies which can be used for the treatment of TB is reviewed. This includes liposomes-based, niosomes-based and microemulsions-based anti-tubercular drug delivery strategies.


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Urgency of novel anti-tuberculosis strategies: a prospective challenge

Abbate E, Vescovo M, Natiello M, Cufré M, García A. 2012. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and Thioridazine. Journal of Antimicrobial agents and Chemotherapy 67, 473-477. http://dx.doi.org/10.1093/jac/dkr500

Ahmed M, Ramadan W, Rambhu D, Shakeel F. 2008. Potential of Nano emulsions for intravenous delivery of rifampicin. Pharmazie 63, 806–11.

Amaral L. 2013. Thioridazine as an Adjunct for Therapy of Multi-Drug (MDR), Extensively Drug Resistant (XDR) and Totally Drug Resistant (TDR) Pulmonary Tuberculosis Infections. Mycobacterial Diseases 3, 2. http://dx.doi.org/10.4172/2161-1068.1000e120

Amaral L, Molnar J. 2012. Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis.  Expert Review of Anti-Infective Therapy 10, 869-873.

Andries K, Verhasselt  P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, VanGestel J, Timmerman P, Zhu M, Lee E, Williams P,  Chaffoy D, Huitric E, HoffnerS, 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. http://dx.doi.org/10.1126/science.1106753

Anh TT, Watson EE, Pujari V, Conroy T, Dowman LJ, Giltrap AM, Pang A, Wong WR, Linington RG, Mahapatra S. 2017. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nature Communications 8, 14414.

Arora K, Ochoa-Montano B, Tsang PS, Blundell TL, Dawes SS, Mizrahi V, Bayliss T, Mackenzie CJ, Cleghorn LA, Ray PC, Wyatt PG, Uh E, Lee J, Barry CE, Boshoff HI. 2014. Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 58, 6962-6965.

Arya N, Raut MK, Tekale SG, Shishoo CJ, Jain KS. 2014. Tuberculosis: New drug discovery pipelines. Austin Journal of Analytical and Pharmaceutical Chemistry 1, 1-9.

Baldwin PR, Reeves AZ, Powell KR, Napier RJ, Swimm AI, Sun A. 2015. Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis. European Journal of Medicinal Chemistry 92, 693-699. http://dx.doi.org/10.1016/j.ejmech.2015.01.020

Centis R, Dara M, Matteelli A, Blasi F, Migliori GB. 2014. ERS/WHO tuberculosis consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use. European Respiratory Journal 44, 811–815. http://dx.doi.org/10.1183/09031936.00060414

Chandran M, Renuka J, Sridevi JP, Ganesh S, Pedgaonka GS, Asmitha V, Yogeeswari P, Sriram D. 2015. Benzothiazinone-piperazine derivatives as efficient Mycobacterium tuberculosis DNA gyrase inhibitors. International Journal of Mycobacteriology 4(2), 104–111. http://dx.doi.org/10.1016/j.ijmyco.2015.02.002

Cohen KA, Bishai WR, Pym AS. 2014. Molecular basis of drug resistance in Mycobacterium tuberculosis. Microbiol spectrum 2(3), 1-16. http://dx.doi.org/10.1128/microbiolspec.MGM2-0036-2013.

Danielsson I, Lindman B. 1981. The definition of microemulsion. Colloids and Surfaces 33(4), 391–392.

Davis ME, Chen ZG, Shin DM. 2008. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews Drug Discovery 7(9), 771-782.

Deol P, Khuller GK. 1997. Lung specific stealth liposomes: stability, biodistribution and toxicity of liposomal antitubercular drugs in mice. Biochimica et Biophysica Acta 1334(2-3), 161–172.

Deol P, Khuller GK, JoshiK. 1997. Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice. Antimicrobial Agents and Chemotherapy 41(6), 1211–1214.

Diekema DJ, Jones RN. 2001. Oxazolidinone antibiotics. Lancet 358, 1975–1982.

Dover LG, Coxon GD. 2011. Current status and research strategies in tuberculosis drug development. Journal of Medical Chemistry 54, 6157–6165. http://dx.doi.org/10.1021/jm200305q

El-Ridy MS, Abdelbary A, Nasr EA, Khalil RM, Mostafa DM, El-Batal AI, El-Alim SHA. 2011. Niosomal encapsulation of the antitubercular drug pyrazinamide. Drug Development and Industrial Pharmacy 37, 1110–1118. https://doi.org/10.3109/03639045.2011.560605

Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C.2003. Tuberculosis. Lancet 362(9387), 887-899.

Ginsburg AS, Grosset JH, Bishai WR. 2003. Fluoroquinolones, tuberculosis and   resistance. The Lancet Infectious Diseases 3(7), 432-442.

Griffiths G, Nyström B, Sable SB, Khuller GK. 2010. Nanobead-based interventions for the treatment and prevention of tuberculosis. Nature Reviews Microbiology 8(11), 827–828. https://doi.org/10.1038/nrmicro2437

Hoagland DT, Liu J, Lee RB, Lee RE. 2016. New agents for the treatment of drug-resistant Mycobacterium tuberculosis Advanced Drug Delivery Reviews 102, 55-72.

Ioerger TR, O’Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, Murphy KC, Boshoff  HI, Mizrahi V, Rubin EJ, Sassetti CM, Barry CE, Sherman DR, Parish T, Sacchettini JC. 2013. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One 8(9), e75245. https://doi.org/10.1371/journal.pone.0075245

Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D. 2013. Thiazole-aminopiperidine hybrid analogues: Design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors. European Journal of Medicinal Chemistry 70, 143–153.

Johnson R, Streicher E, Louw G, Warren RM, van-Helden PD, Victorm TC. 2006. Drug resistance in Mycobacterium tuberculosis. Current Issues in Molecular Biology 8, 97-111.

KarkiR, Mamatha GC, Subramanya G, Udupa N. 2008. Preparation, characterization and tissue disposition of niosomes containing isoniazid. Rasayan Journal of Chemistry 1(2), 224–227.

Kaysser L, Lutsch L, Siebenberg S, Wemakor E, Kammerer B, Gust B. 2009. Identification and manipulation of the caprazamycin gene cluster lead to new simplified liponucleoside antibiotics and give insights into the biosynthetic pathway.The Journal of Biological Chemistry 284(22), 14987-14996. https://doi.org/10.1074/jbc.M901258200

Keshavjee S, Farmer PE. 2012. Tuberculosis, drug resistance, and the history of modern medicine. The New England journal of medicine 367, 931–936. https://doi.org/10.1056/NEJMra1205429.

Khuller GK, Kapur M, Sharma S. 2004. Liposome technology for drug delivery against Mycobacterial infections. Current Pharmaceutical Design 10(26), 3263–3274.

Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, Zaburannyi N, Herrmann J, Wenzel SC, Konig C, Ammerman NC, Barrio MB. 2015. Antibiotics Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348(6239), 1106-1112. https://doi.org/10.1126/science.aaa4690

Kreuter J. 2004. Nanoparticles as drug delivery system. American Scientific Publishers 7, 161–180.

Kumar S. 2011. Analysis of TX-100 based micro emulsion in the presence of TB drug isoniazid. Rourkela: Lancet 362, 887.

Lawrence MJ, Rees GD. 2000. Micro emulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews 45(1), 89–121.

Ling LL, Schneide T, Peoples AJ, Spoering AL, Engels LI, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K. 2015:Erratum: A new antibiotic kills pathogens without detectable resistance. Nature 517(7535), 455-459. https://doi.org/10.1038/nature14303

Loddenkemper R, Hauer B. 2010. Drug-resistant tuberculosis: a worldwide epidemic poses a new challenge. Deutches Arzteblatt International 107, 10–19. https://doi.org/10.3238/arztebl.2010.0010

Luciani F, Sisson SA, Jiang H, Francis AR, Tanaka MM. 2009. The epidemiological fitness cost of drug resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 106, 14711–14715.

Makarov V, Lechartier B, Zhang M, Neres J, van der Sar AM, Raadsen SA, Hartkoorn RC, Ryabova OB, Vocat A, Decosterd LA, Widmer N, Buclin T, Bitter W, Andries K, Pojer F, Dyson PJ, Cole ST. 2014. Towards a new combination therapy for tuberculosis with next generation benzothiazinones: EMBO Molecular Medicine 6(3), 372-383.

Manjunatha U, Boshoff HI, Barry CE. 2009. The mechanism of action of PA-824: Novel insights from transcriptional profiling. Communicative and Integrative Biology 2, 215–218.

Klopper MWarren RMHayes CGey van Pittius NCStreicher EMMüller BSirgel FAChabula-Nxiweni MHoosain ECoetzee GDavid van Helden PVictor TCTrollip AP. 2013. Emergence and spread of extensively and totally drug-resistant tuberculosis: South Africa. Emergence of Infectious Diseases 19, 449-455. https://doi.org/10.3201/EID1903.120246.

Matteelli A, Carvalho AC, Dooley KE, Kritski A. 2010. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiology 5(6), 849–858.

Maus CE, Pilkaytis BB, Shinnick TM. 2005. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin and viomycin in Mycobacterium tuberculosis. Antimicrobial agents and Chemotherapy 49, 3192-3197.

Maus CE, Pilkaytis BB, Shinnick TM. 2005. Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 49, 571-577.

Mdluli K, Kaneko T, Upton A. 2015. The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harbor Perspectives in Medicine 5(6), a021154. https://doi.org/10.1101/cshperspect.a021154

Mehta SK, Kaur G, Bhasin KK. 2007. Analysis of Tween based micro emulsion in the presence of TB drug rifampicin. Colloids and Surfaces. B, Biointerfaces 60(1), 95–104.

Mehta SP, Jindal N. 2013. Formulation of Tyloxapolniosomes for encapsulation, stabilization and dissolution of anti-tubercular drugs. Colloids and Surfaces B, Biointerfaces 101, 434–441.

MitnickCD, Castro KG, Harrington M, Sacks LV, Burman W. 2007. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PloSMedicine 4(11), e292. https://doi.org/10.1371/journal.pmed.0040292.

Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR, Marra F. 2007. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs 67(14), 2077-2099.

Moretton MA, Glisoni RJ, Chiappetta DA, Sosnik A. 2010. Molecular implications in the nanoencapsulation of the anti-tuberculosis drug rifampicin within flower-like polymeric micelles. Colloids and Surfaces B, Biointerfaces 79(2), 467–479.

Morlock GP, Metchock B, Sikes S, Crawford JT, Cooksey RC. 2003. ethA, inhA, and katGloci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates Antimicrobial  Agents and Chemotherapy 47, 3799-805. https://doi.org/10.1128/AAC.47.12.3799-3805.2003

Muller RH, Mehnert W, Lucks JS. 1995. Solid lipid nanoparticles (SLN) an alternative colloidal carrier system for controlled drug delivery. European Journal of Pharmaceutics and Biopharmaceutics 41(1), 62–69.

Munro SA, Lewin SA, Smith HJ, Engel ME, Fretheim A, Volmink J. 2007. Patient adherence to tuberculosis treatment: A systematic review of qualitative research. PLoS Medicine 4, e238. https://doi.org/10.1371/journal.pmed.0040238

Okada M, Kobayashi K. 2007. Recent progress in Mycobacteriology. Kekkaku 82(10), 783-799.

Palomino J, Martin A. 2014. Drug resistance mechanisms in Mycobacterium tuberculosis. Antibiotics 3, 317-340. http://doi.org/10.3390/antibiotics3030317

Paranjpe M, Müller-Goymann CC. 2014. Nanoparticle-mediated pulmonary drug delivery: A review. International Journal of Molecular Sciences 15, 5852–5873. http://doi.org/10.3390/ijms15045852

Parida SK, Axelsson-Robertson R, Rao MV, Singh N, Master I, Lutckii A, Keshavjee S, Andersson J, Zumla A, Maeurer M. 2015. Totally drug-resistant tuberculosis and adjunct therapies. Journal of International Medicine 277(4), 388-405. http://doi.org/10.1111/joim.12264

Pastoriza LC, Todoroff J, Vanbever R. 2014. Delivery strategies for sustained drug release in the lungs. AdvanceDrug Delivery Reviews 75, 81–91.

Podany AT, Swindells S. 2016. Current strategies to treat tuberculosis. F1000 Faculty Review-2579. http://doi.org/10.12688/f1000research.7403.1

Ramaswamy S, Musser JM. 1998. Molecular genetics basis of antimicrobialagent resistance in Mycobacterium tuberculosis: 1998 update. Tuberculosis Lung Diseases 79, 3-29.

Rani NP, Suriyaprakash TNK, Senthamarai R. 2010. Formulation and evaluation of rifampicin and gatifloxacin niosomes on logarithmic-phase cultures of Mycobacterium tuberculosis. International Journal of Pharma and Bio Sciences 1(4), 379–387.

Rao SP, Lakshminarayana SB, Kondreddi RR, Herve M, Camacho LR, Bifani P, Kalapala SK, Jiricek J, Ma NL, Tan BH, Ng SH, Nanjundappa M. 2013. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Science Translational Medicine 5(214), 168. http://doi.org/10.1126/scitranslmed.3007355

Raviglione MC, Uplekar M. 2014. WHO’s new Stop TB strategy? Lancet 367, 952–955.

Rothstein DM, Shalish C, Murphy CK, Sternlicht A, Campbell LA. 2006 Development potential of Rifalazil and other benzoxazinorifamycins. Expert Opinionon Investigational Drugs 15, 603-623. https://doi.org/10.1517/13543784.15.6.603

Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, Cole ST. 2015. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nature Communications 6(7659), 1-8.

Sacksteder KA, Protopopova M, Barry CE, Andries K, Nacy CA. 2012.Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future Microbiology 7(7), 823-837.

Safi H, Sayers B, Hazbon MH, Allan D. 2008. Transfer of embB codon 306 mutations into clinical Mycobacterium tuberculosis strains alters susceptibility to ethambutol, isoniazid and rifampin. Antimicrobial Agents and Chemotherapy. 52(6), 2027-2034 http://doi.org/10.1128/AAC.01486-07.

Sarciaux JM, Acar L, Sado PA. 1995. Using micro emulsion formulations for oral drug delivery of therapeutic peptides. International Journal of Pharmaceutics 120(2), 127–136.

Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S. 2010. Linezolid in the treatment of multidrug-resistant tuberculosis. Clinical Infectious Diseases 50(1), 49-55.

Scorpio A, Zhang Y. 1996. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nature Medicine 2, 662-667.

Sekiguchi, JI, Nakamura T, Miyoshi-Akiyam T. 2007. Development and evaluation of a line probe assay for rapid identification of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis strains. Journal of Clinical Microbiology 45(9), 2802-2807.

Sharma SK, Liu JJ. 2006. Progress of DOTS in global tuberculosis control. Lancet 367, 950–952. http://doi.org/10.1016/S0140-6736(06)68391-8

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. 2008. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 322(5906), 1392-1395.

Singh V, Donini S, Pacitto A, Sala C, Hartkoorn RC, DharN, Keri G, Ascher DV, Mondésert G, Vocat A, Lupien A. 2017.The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis. ACS Infectious Diseases 3(1), 5–17. http://doi.org/10.1021/acsinfecdis.6b00102

Sloan DJ, Davies GR, Khoo SH.  2013. Recent advances in tuberculosis: new drugs and treatment regimens. Current Respiratory Medicine Reviews 9, 200–210.

Stanley SA, Kawate T, Iwase N, Shimizu M, Clatworthy AE, Kazyanskaya E, Sacchettini JC, Ioerger TR, Siddiqi NA, Minami S, Aquadro JA, Grant SS, Rubin EJ, Hung DT. 2013. Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proceedings of the National Academy of Sciences of the United States of America 110(28), 11565-11570. http://doi.org/10.1073/pnas.1302114110

Starks AM, Gumusboga A, Plikaytis BB, Shinnick TM, Posey JE. 2009. Mutations at embB codon 306 are an important molecular indicator of ethambutol resistance in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 53(3), 1061-1066.

Telenti A, Imboden P, Marchesi F. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341, 647-650.

Thomas S, Bagyalakshmi J. 2013. Design, development and characterization of pyrazinamide niosomal dosage form. American Journal of Pharmtech Research 3(6), 532–544.

Uchegbu F, Vyas SP. 1998.  Non-ionic surfactant based vesicles (niosomes) in drug delivery: International Journal of Pharmaceutics 172(s1-2), 33–70. http://doi.org/10.1016/S0378-5173(98)00169-0

Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. 2012. Totally drug-resistant tuberculosis in India. Clinical Infectious Disease 54, 579–581.

Van Ingen J, van der Laan T, Amaral L, Dekhuijzen R, Boeree MJ. 2009. In vitro activity of Thioridazine against Mycobacteria. International Journal of Antimicrobial Agents 34, 190-191.

Vilcheze C, Wang F, Arai M, Hazbón MH, Colangeli RKremer LWeisbrod TRAlland DSacchettini JCJacobs WR Jr. 2006. Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nature Medicine 12(9), 1027-1029.

World Health Organization. 2010.  Multidrug and Extensively Drug-resistant TB (M/XDR-TB) Global Report on Surveillance and Response.

Xavier AS, Lakshmanan M. 2014. Delamanid: A new armor in combating drug-resistant tuberculosis. Journal of Pharmacology and Pharmacotherapeutics 5(3), 222–224. http://doi.org/10.4103/0976-500X.136121

Zhang Y, Heym B, Allen B, Young D, Cole ST. 1992. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358(6387), 591-593. http://doi.org/10.1038/358591a0

Zheng H, Colvin CJ, Johnson BK, Kirchhoff  PD, Wilson M, Jorgensen-Muga K, Larsen SD, Abramovitch RB. 2016. Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nature Chemical Biology 13(2), 218-225.

Zumla A, Hafner R, Lienhardt C, Hoelscher M, Nunn A. 2012. Advancing the development of tuberculosis therapy. Nature Reviews Drug Discovery 11, 171–172. http://doi.org/10.1038/nrd3694.


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