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Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

General Review Article

Collocating Novel Targets for Tuberculosis (TB) Drug Discovery

Author(s): Karan Gandhi and Mehul Patel*

Volume 18, Issue 2, 2021

Published on: 21 January, 2020

Page: [307 - 316] Pages: 10

DOI: 10.2174/1570163817666200121143036

Price: $65

Abstract

Background: Mycobacterium tuberculosis, being a resistive species is an incessant threat to the world population for the treatment of Tuberculosis (TB). An advanced genetic or a molecular level approach is mandatory for both diagnosis and therapy as the prevalence of multi drug-resistant (MDR) and extensively drug- resistant (XDR) TB.

Methods: A literature review was conducted, focusing essentially on the development of biomarkers and targets to extrapolate the Tuberculosis Drug Discovery process.

Results and Discussion: In this article, we have discussed several substantial targets and genetic mutations occurring in a diseased or treatment condition of TB patients. It includes expressions in Bhlhe40, natural resistance associated macrophage protein 1 (NRAMP1) and vitamin D receptor (VDR) with its mechanistic actions that have made a significant impact on TB. Moreover, recently identified compounds; imidazopyridine amine derivative (Q203), biphenyl amide derivative (DG70), azetidine, thioquinazole, tetrahydroindazole and 2- mercapto- quinazoline scaffolds for several targets such as adenosine triphosphate (ATP), amino acid and fatty acid have been briefed for their confirmed hits and therapeutic activity.

Keywords: Adenosine triphosphate (ATP), amino acid, fatty acid, interferon- γ, Interleukin-10, natural resistance associated macrophage protein 1 (NRAMP1).

Graphical Abstract
[1]
Quan D, Nagalingam G, Payne R, Triccas JA. New tuberculosis drug leads from naturally occurring compounds. Int J Infect Dis 2017; 56: 212-20.
[http://dx.doi.org/10.1016/j.ijid.2016.12.024] [PMID: 28062229]
[3]
Mdluli K, Spigelman M. Novel targets for tuberculosis drug discovery. Curr Opin Pharmacol 2006; 6(5): 459-67.
[http://dx.doi.org/10.1016/j.coph.2006.06.004] [PMID: 16904376]
[4]
Mdluli K, Kaneko T, Upton A. The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harb Perspect Med 2015; 5(6)a021154
[http://dx.doi.org/10.1101/cshperspect.a021154] [PMID: 25635061]
[5]
Sridhar S, Dash P, Guruprasad K. Comparative analyses of the proteins from Mycobacterium tuberculosis and human genomes: Identification of potential tuberculosis drug targets. Gene 2016; 579(1): 69-74.
[http://dx.doi.org/10.1016/j.gene.2015.12.054] [PMID: 26762852]
[6]
Kinnings SL, Xie L, Fung KH, Jackson RM, Xie L, Bourne PE. The Mycobacterium tuberculosis drugome and its polypharmacological implications. PLOS Comput Biol 2010; 6(11)e1000976
[http://dx.doi.org/10.1371/journal.pcbi.1000976] [PMID: 21079673]
[7]
Irschik H, Reichenbach H, Höfle G, Jansen R. The thuggacins, novel antibacterial macrolides from Sorangium cellulosum acting against selected Gram-positive bacteria. J Antibiot (Tokyo) 2007; 60(12): 733-8.
[http://dx.doi.org/10.1038/ja.2007.95] [PMID: 18276996]
[8]
Truong NB, Pham CV, Doan HT, et al. Antituberculosis cycloartane triterpenoids from Radermachera boniana. J Nat Prod 2011; 74(5): 1318-22.
[http://dx.doi.org/10.1021/np200022b] [PMID: 21469696]
[9]
Yagi A, Uchida R, Hamamoto H, Sekimizu K, Kimura KI, Tomoda H. Anti-Mycobacterium activity of microbial peptides in a silkworm infection model with Mycobacterium smegmatis. J Antibiot (Tokyo) 2017; 70(5): 685-90.
[http://dx.doi.org/10.1038/ja.2017.23] [PMID: 28446822]
[10]
Medapati RV. Modern Genetics in Combating Tuberculosis. J Genet Genomics 2017.1e103
[12]
Sukheja P, Kumar P, Mittal N, et al. A novel small-molecule inhibitor of the Mycobacterium tuberculosis demethylmenaquinone Methyltransferase MenG is bactericidal to both growing and nutritionally deprived persister cells. MBio 2017; 8(1): e02022-16.
[http://dx.doi.org/10.1128/mBio.02022-16] [PMID: 28196957]
[13]
Hamamoto H, Urai M, Ishii K, et al. Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane. Nat Chem Biol 2015; 11(2): 127-33.
[http://dx.doi.org/10.1038/nchembio.1710] [PMID: 25485686]
[14]
Monzingo AF, Gao J, Qiu J, Georgiou G, Robertus JD. The X-ray structure of Escherichia coli RraA (MenG), A protein inhibitor of RNA processing. J Mol Biol 2003; 332(5): 1015-24.
[http://dx.doi.org/10.1016/S0022-2836(03)00970-7] [PMID: 14499605]
[15]
Beamer GL, Flaherty DK, Assogba BD, et al. Interleukin-10 promotes Mycobacterium tuberculosis disease progression in CBA/J mice. J Immunol 2008; 181(8): 5545-50.
[http://dx.doi.org/10.4049/jimmunol.181.8.5545] [PMID: 18832712]
[16]
Huynh JP, Lin CC, Kimmey JM, et al. Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection. J Exp Med 2018; 215(7): 1823-38.
[http://dx.doi.org/10.1084/jem.20171704] [PMID: 29773644]
[17]
Lin CC, Bradstreet TR, Schwarzkopf EA, et al. Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation. Nat Commun 2014; 5: 3551.
[http://dx.doi.org/10.1038/ncomms4551] [PMID: 24699451]
[18]
Li X, Yang Y, Zhou F, et al. SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS One 2011; 6(1)e15831
[http://dx.doi.org/10.1371/journal.pone.0015831] [PMID: 21283567]
[19]
Gabryšová L, O’Garra A. Regulating the regulator: Bhlhe40 directly keeps IL-10 in check
[20]
Canonne-Hergaux F, Gruenheid S, Govoni G, Gros P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc Assoc Am Physicians 1999; 111(4): 283-9.
[http://dx.doi.org/10.1046/j.1525-1381.1999.99236.x] [PMID: 10417735]
[21]
Blackwell JM, Goswami T, Evans CA, et al. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol 2001; 3(12): 773-84.
[http://dx.doi.org/10.1046/j.1462-5822.2001.00150.x] [PMID: 11736990]
[22]
Goswami T, Bhattacharjee A, Babal P, et al. Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter. Biochem J 2001; 354(Pt 3): 511-9.
[http://dx.doi.org/10.1042/bj3540511] [PMID: 11237855]
[23]
Medapati RV, Suvvari S, Godi S, Gangisetti P. NRAMP1 and VDR gene polymorphisms in susceptibility to pulmonary tuberculosis among Andhra Pradesh population in India: a case-control study. BMC Pulm Med 2017; 17(1): 89.
[http://dx.doi.org/10.1186/s12890-017-0431-5] [PMID: 28583097]
[24]
Wilbur AK, Kubatko LS, Hurtado AM, Hill KR, Stone AC. Vitamin D receptor gene polymorphisms and susceptibility M. tuberculosis in native Paraguayans. Tuberculosis (Edinb) 2007; 87(4): 329-37.
[http://dx.doi.org/10.1016/j.tube.2007.01.001] [PMID: 17337247]
[25]
Fernández-Mestre M, Villasmil Á, Takiff H, Fuentes Alcalá Z. NRAMP1 and VDR gene polymorphisms in susceptibility to tuberculosis in Venezuelan population. Dis Markers 2015; 2015
[26]
Hu Q, Chen Z, Liang G, et al. Vitamin D receptor gene associations with pulmonary tuberculosis in a Tibetan Chinese population. BMC Infect Dis 2016; 16(1): 469.
[http://dx.doi.org/10.1186/s12879-016-1699-4] [PMID: 27595605]
[27]
Lee SW, Chuang TY, Huang HH, Liu CW, Kao YH, Wu LS. VDR and VDBP genes polymorphisms associated with susceptibility to tuberculosis in a Han Taiwanese population. J Microbiol Immunol Infect 2016; 49(5): 783-7.
[http://dx.doi.org/10.1016/j.jmii.2015.12.008] [PMID: 26869016]
[28]
Merza M, Farnia P, Anoosheh S, et al. The NRAMPI, VDR and TNF-α gene polymorphisms in Iranian tuberculosis patients: the study on host susceptibility. Braz J Infect Dis 2009; 13(4): 252-6.
[PMID: 20231985]
[29]
Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys 2012; 523(1): 123-33.
[http://dx.doi.org/10.1016/j.abb.2012.04.001] [PMID: 22503810]
[30]
Laplana M, Royo JL, Fibla J, Vitamin D, Vitamin D. Receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene 2018; 678: 384-94.
[http://dx.doi.org/10.1016/j.gene.2018.08.017] [PMID: 30092343]
[31]
Daiger SP, Sullivan LS, Bowne SJ. Genetic Mechanisms of Retinal Disease. 5th ed. InRetina 2013; pp. 624-34.
[32]
Twyman RM. Single-nucleotide polymorphism (SNP) analysis Encyclopedia of Neurosci 2009 Jan; 18: 881-5.
[33]
Walter MR. Structure of IFNγ and its Receptors. InHandbook of Cell Signaling 2010 Jan; 1261-3.
[http://dx.doi.org/10.1016/B978-0-12-374145-5.00039-5]
[34]
Boguniewicz M, Fonacier L, Leung DY. Atopic and Contact Dermatitis. 5th ed. InClinical Immunology 2019; pp. 611-24.
[35]
Mason RC, Murray JF, Nadel JA, Gotway M. Murray & Nadel's Textbook of Respiratory Medicine E-Book. Elsevier Health Sci 2015 Mar;
[36]
Adams JF, Schölvinck EH, Gie RP, Potter PC, Beyers N, Beyers AD. Decline in total serum IgE after treatment for tuberculosis. Lancet 1999; 353(9169): 2030-3.
[http://dx.doi.org/10.1016/S0140-6736(98)08510-9] [PMID: 10376618]
[37]
Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleukin-4 and interleukin-10 production by T helper cells reveals intact Th1 and regulatory TR1 cell activation and a delay of the Th2 cell response in equine neonates and foals. Vet Res 2010; 41(4): 47.
[http://dx.doi.org/10.1051/vetres/2010019] [PMID: 20374696]
[38]
Leung DY, Boguniewicz M. Atopic Dermatitis and Allergic Contact Dermatitis. InMiddleton's Allergy Essentials 2017; pp. 265-300.
[39]
Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383(6603): 787-93.
[http://dx.doi.org/10.1038/383787a0] [PMID: 8893001]
[40]
Ohrui T, Zayasu K, Sato E, Matsui T, Sekizawa K, Sasaki H. Pulmonary tuberculosis and serum IgE. Clin Exp Immunol 2000; 122(1): 13-5.
[http://dx.doi.org/10.1046/j.1365-2249.2000.01291.x] [PMID: 11012611]
[41]
Wigginton JE, Kirschner D. A model to predict cell-mediated immune regulatory mechanisms during human infection with Mycobacterium tuberculosis. J Immunol 2001; 166(3): 1951-67.
[http://dx.doi.org/10.4049/jimmunol.166.3.1951] [PMID: 11160244]
[42]
Nakayama T, Hirahara K, Onodera A, et al. Th2 cells in health and disease. Annu Rev Immunol 2017; 35: 53-84.
[http://dx.doi.org/10.1146/annurev-immunol-051116-052350] [PMID: 27912316]
[43]
Babu S, Nutman TB. Helminth-tuberculosis co-infection: an immunologic perspective. Trends Immunol 2016; 37(9): 597-607.
[http://dx.doi.org/10.1016/j.it.2016.07.005] [PMID: 27501916]
[44]
Lang R, Schick J. Review: Impact of Helminth Infection on Antimycobacterial Immunity-A Focus on the Macrophage. Front Immunol 2017; 8: 1864.
[http://dx.doi.org/10.3389/fimmu.2017.01864] [PMID: 29312343]
[45]
Lee K, Gudapati P, Dragovic S, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010; 32(6): 743-53.
[http://dx.doi.org/10.1016/j.immuni.2010.06.002] [PMID: 20620941]
[46]
Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 2012; 249(1): 43-58.
[http://dx.doi.org/10.1111/j.1600-065X.2012.01152.x] [PMID: 22889214]
[47]
Lamprecht DA, Finin PM, Rahman MA, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun 2016; 7: 12393.
[http://dx.doi.org/10.1038/ncomms12393] [PMID: 27506290]
[48]
Iqbal IK, Bajeli S, Akela AK, Kumar A. Bioenergetics of Mycobacterium: an emerging landscape for drug discovery. Pathogens 2018; 7(1): 24.
[http://dx.doi.org/10.3390/pathogens7010024] [PMID: 29473841]
[49]
Hoagland DT, Liu J, Lee RB, Lee RE. New agents for the treatment of drug-resistant Mycobacterium tuberculosis. Adv Drug Deliv Rev 2016; 102: 55-72.
[http://dx.doi.org/10.1016/j.addr.2016.04.026] [PMID: 27151308]
[50]
Olaru ID, Heyckendorf J, Andres S, Kalsdorf B, Lange C. Bedaquiline-based treatment regimen for multidrug-resistant tuberculosis. Eur Respir J 2017; 49(5)1700742
[http://dx.doi.org/10.1183/13993003.00742-2017] [PMID: 28529207]
[51]
Bald D, Villellas C, Lu P, Koul A. Targeting energy metabolism in Mycobacterium tuberculosis, a new paradigm in antimycobacterial drug discovery. MBio 2017; 8(2): e00272-17.
[http://dx.doi.org/10.1128/mBio.00272-17] [PMID: 28400527]
[52]
Pethe K, Bifani P, Jang J, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 2013; 19(9): 1157-60.
[http://dx.doi.org/10.1038/nm.3262] [PMID: 23913123]
[53]
Lu P, Lill H, Bald D. ATP synthase in mycobacteria: special features and implications for a function as drug target. Biochim Biophys Acta 2014; 1837(7): 1208-18.
[http://dx.doi.org/10.1016/j.bbabio.2014.01.022] [PMID: 24513197]
[54]
Ahmad Z, Okafor F, Azim S, Laughlin TF. ATP synthase: a molecular therapeutic drug target for antimicrobial and antitumor peptides. Curr Med Chem 2013; 20(15): 1956-73.
[http://dx.doi.org/10.2174/0929867311320150003] [PMID: 23432591]
[55]
Ahmad Z, Okafor F, Laughlin TF. Role of charged residues in the catalytic sites of Escherichia coli ATP synthase. J Amino Acids 2011.2011785741
[http://dx.doi.org/10.4061/2011/785741] [PMID: 22312470]
[56]
Haagsma AC. Respiratory ATP synthesis as drug target for combating tuberculosis
[57]
Awasthy D, Ambady A, Narayana A, Morayya S, Sharma U. Roles of the two type II NADH dehydrogenases in the survival of Mycobacterium tuberculosis in vitro. Gene 2014; 550(1): 110-6.
[http://dx.doi.org/10.1016/j.gene.2014.08.024] [PMID: 25128581]
[58]
Sellamuthu S, Singh M, Kumar A, Singh SK. Type-II NADH Dehydrogenase (NDH-2): a promising therapeutic target for antitubercular and antibacterial drug discovery. Expert Opin Ther Targets 2017; 21(6): 559-70.
[http://dx.doi.org/10.1080/14728222.2017.1327577] [PMID: 28472892]
[59]
Murugesan D, Ray PC, Bayliss T, et al. 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization. ACS Infect Dis 2018; 4(6): 954-69.
[http://dx.doi.org/10.1021/acsinfecdis.7b00275] [PMID: 29522317]
[60]
Harbut MB, Yang B, Liu R, et al. Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity. Angew Chem Int Ed Engl 2018; 57(13): 3478-82.
[http://dx.doi.org/10.1002/anie.201800260] [PMID: 29388301]
[61]
Ventura M, Rieck B, Boldrin F, et al. GarA is an essential regulator of metabolism in Mycobacterium tuberculosis. Mol Microbiol 2013; 90(2): 356-66.
[PMID: 23962235]
[62]
Tullius MV, Harth G, Horwitz MA. Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Infect Immun 2003; 71(7): 3927-36.
[http://dx.doi.org/10.1128/IAI.71.7.3927-3936.2003] [PMID: 12819079]
[63]
Rieck B, Degiacomi G, Zimmermann M, et al. PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis. PLoS Pathog 2017; 13(5)e1006399
[http://dx.doi.org/10.1371/journal.ppat.1006399] [PMID: 28545104]
[64]
Zhang YJ, Reddy MC, Ioerger TR, et al. Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 2013; 155(6): 1296-308.
[http://dx.doi.org/10.1016/j.cell.2013.10.045] [PMID: 24315099]
[65]
Wellington S, Nag PP, Michalska K, et al. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. Nat Chem Biol 2017; 13(9): 943-50.
[http://dx.doi.org/10.1038/nchembio.2420] [PMID: 28671682]
[66]
Nazarova EV, Montague CR, La T, et al. Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis. eLife 2017.6e26969
[http://dx.doi.org/10.7554/eLife.26969] [PMID: 28708968]
[67]
Wright HT, Reynolds KA. Antibacterial targets in fatty acid biosynthesis. Curr Opin Microbiol 2007; 10(5): 447-53.
[http://dx.doi.org/10.1016/j.mib.2007.07.001] [PMID: 17707686]
[68]
Young K, Jayasuriya H, Ondeyka JG, et al. Discovery of FabH/FabF inhibitors from natural products. Antimicrob Agents Chemother 2006; 50(2): 519-26.
[http://dx.doi.org/10.1128/AAC.50.2.519-526.2006] [PMID: 16436705]
[69]
Gurvitz A, Hiltunen JK, Kastaniotis AJ. Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae. Appl Environ Microbiol 2008; 74(16): 5078-85.
[http://dx.doi.org/10.1128/AEM.00655-08] [PMID: 18552191]
[70]
Marrakchi H, Lanéelle G, Quémard AK. InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 2000; 146(Pt 2): 289-96.
[http://dx.doi.org/10.1099/00221287-146-2-289] [PMID: 10708367]
[71]
Tseng ST, Tai CH, Li CR, Lin CF, Shi ZY. The mutations of katG and inhA genes of isoniazid-resistant Mycobacterium tuberculosis isolates in Taiwan. J Microbiol Immunol Infect 2015; 48(3): 249-55.
[http://dx.doi.org/10.1016/j.jmii.2013.08.018] [PMID: 24184004]
[72]
Campaniço A, Moreira R, Lopes F. Drug discovery in tuberculosis. New drug targets and antimycobacterial agents. Eur J Med Chem 2018; 150: 525-45.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.020] [PMID: 29549838]
[73]
Manjunatha UHS, Rao SP, Kondreddi RR, et al. Direct inhibitors of InhA are active against Mycobacterium tuberculosis. Sci Transl Med 2015; 7(269)269ra3
[http://dx.doi.org/10.1126/scitranslmed.3010597] [PMID: 25568071]

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