Generic placeholder image

Current Drug Discovery Technologies


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


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
Quan D, Nagalingam G, Payne R, Triccas JA. New tuberculosis drug leads from naturally occurring compounds. Int J Infect Dis 2017; 56: 212-20.
[] [PMID: 28062229]
Mdluli K, Spigelman M. Novel targets for tuberculosis drug discovery. Curr Opin Pharmacol 2006; 6(5): 459-67.
[] [PMID: 16904376]
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
[] [PMID: 25635061]
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.
[] [PMID: 26762852]
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
[] [PMID: 21079673]
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.
[] [PMID: 18276996]
Truong NB, Pham CV, Doan HT, et al. Antituberculosis cycloartane triterpenoids from Radermachera boniana. J Nat Prod 2011; 74(5): 1318-22.
[] [PMID: 21469696]
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.
[] [PMID: 28446822]
Medapati RV. Modern Genetics in Combating Tuberculosis. J Genet Genomics 2017.1e103
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.
[] [PMID: 28196957]
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.
[] [PMID: 25485686]
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.
[] [PMID: 14499605]
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.
[] [PMID: 18832712]
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.
[] [PMID: 29773644]
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.
[] [PMID: 24699451]
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
[] [PMID: 21283567]
Gabryšová L, O’Garra A. Regulating the regulator: Bhlhe40 directly keeps IL-10 in check
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.
[] [PMID: 10417735]
Blackwell JM, Goswami T, Evans CA, et al. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol 2001; 3(12): 773-84.
[] [PMID: 11736990]
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.
[] [PMID: 11237855]
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.
[] [PMID: 28583097]
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.
[] [PMID: 17337247]
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
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.
[] [PMID: 27595605]
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.
[] [PMID: 26869016]
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]
Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys 2012; 523(1): 123-33.
[] [PMID: 22503810]
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.
[] [PMID: 30092343]
Daiger SP, Sullivan LS, Bowne SJ. Genetic Mechanisms of Retinal Disease. 5th ed. InRetina 2013; pp. 624-34.
Twyman RM. Single-nucleotide polymorphism (SNP) analysis Encyclopedia of Neurosci 2009 Jan; 18: 881-5.
Walter MR. Structure of IFNγ and its Receptors. InHandbook of Cell Signaling 2010 Jan; 1261-3.
Boguniewicz M, Fonacier L, Leung DY. Atopic and Contact Dermatitis. 5th ed. InClinical Immunology 2019; pp. 611-24.
Mason RC, Murray JF, Nadel JA, Gotway M. Murray & Nadel's Textbook of Respiratory Medicine E-Book. Elsevier Health Sci 2015 Mar;
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.
[] [PMID: 10376618]
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.
[] [PMID: 20374696]
Leung DY, Boguniewicz M. Atopic Dermatitis and Allergic Contact Dermatitis. InMiddleton's Allergy Essentials 2017; pp. 265-300.
Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383(6603): 787-93.
[] [PMID: 8893001]
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.
[] [PMID: 11012611]
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.
[] [PMID: 11160244]
Nakayama T, Hirahara K, Onodera A, et al. Th2 cells in health and disease. Annu Rev Immunol 2017; 35: 53-84.
[] [PMID: 27912316]
Babu S, Nutman TB. Helminth-tuberculosis co-infection: an immunologic perspective. Trends Immunol 2016; 37(9): 597-607.
[] [PMID: 27501916]
Lang R, Schick J. Review: Impact of Helminth Infection on Antimycobacterial Immunity-A Focus on the Macrophage. Front Immunol 2017; 8: 1864.
[] [PMID: 29312343]
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.
[] [PMID: 20620941]
Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 2012; 249(1): 43-58.
[] [PMID: 22889214]
Lamprecht DA, Finin PM, Rahman MA, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun 2016; 7: 12393.
[] [PMID: 27506290]
Iqbal IK, Bajeli S, Akela AK, Kumar A. Bioenergetics of Mycobacterium: an emerging landscape for drug discovery. Pathogens 2018; 7(1): 24.
[] [PMID: 29473841]
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.
[] [PMID: 27151308]
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
[] [PMID: 28529207]
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.
[] [PMID: 28400527]
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.
[] [PMID: 23913123]
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.
[] [PMID: 24513197]
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.
[] [PMID: 23432591]
Ahmad Z, Okafor F, Laughlin TF. Role of charged residues in the catalytic sites of Escherichia coli ATP synthase. J Amino Acids 2011.2011785741
[] [PMID: 22312470]
Haagsma AC. Respiratory ATP synthesis as drug target for combating tuberculosis
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.
[] [PMID: 25128581]
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.
[] [PMID: 28472892]
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.
[] [PMID: 29522317]
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.
[] [PMID: 29388301]
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]
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.
[] [PMID: 12819079]
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
[] [PMID: 28545104]
Zhang YJ, Reddy MC, Ioerger TR, et al. Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 2013; 155(6): 1296-308.
[] [PMID: 24315099]
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.
[] [PMID: 28671682]
Nazarova EV, Montague CR, La T, et al. Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis. eLife 2017.6e26969
[] [PMID: 28708968]
Wright HT, Reynolds KA. Antibacterial targets in fatty acid biosynthesis. Curr Opin Microbiol 2007; 10(5): 447-53.
[] [PMID: 17707686]
Young K, Jayasuriya H, Ondeyka JG, et al. Discovery of FabH/FabF inhibitors from natural products. Antimicrob Agents Chemother 2006; 50(2): 519-26.
[] [PMID: 16436705]
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.
[] [PMID: 18552191]
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.
[] [PMID: 10708367]
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.
[] [PMID: 24184004]
Campaniço A, Moreira R, Lopes F. Drug discovery in tuberculosis. New drug targets and antimycobacterial agents. Eur J Med Chem 2018; 150: 525-45.
[] [PMID: 29549838]
Manjunatha UHS, Rao SP, Kondreddi RR, et al. Direct inhibitors of InhA are active against Mycobacterium tuberculosis. Sci Transl Med 2015; 7(269)269ra3
[] [PMID: 25568071]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy