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Impact of Target-Based Drug Design in Anti-bacterial Drug Discovery for the Treatment of Tuberculosis

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Structural Bioinformatics: Applications in Preclinical Drug Discovery Process

Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 27))

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is a major public health concern. According to the 2017 WHO report, global burden of TB infection was 10.4 million people causing the mortality rate of ~1.6 million. The rapid emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is of major concern in anti-TB drug discovery. There are different druggable targets and its pathways involved in the virulence, which include Mtb cell wall , replication and transcription, regulatory, protein synthesis, membrane transport, and energy production which need to be explored for efficient killing of the bacteria. The ability of the tubercle bacilli to remain within the host intracellular compartment is of other major concern in TB therapy. Thus, to tackle the TB drug resistance , potent inhibitors with novel mechanism of action of different Mtb druggable targets need to be discovered. Three-dimensional structure of different Mtb target was solved for structure-based drug design . The current chapter focuses on some of the key druggable targets in Mtb and also the recent advances in target-based drug designing in the area of anti-tubercular drug discovery.

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Abbreviations

3D:

Three-dimensional

ag85:

Antigen 85

AMPK:

5′adenosine monophosphate-activated protein kinase

AspS:

Aspartyl tRNA synthetase

BCG:

Bacille Calmette-Guérin

ClpP:

Caseinolytic peptidase P

CmaA1:

Cyclopropane synthase

d-Ala:

d-Alanine

d-Glu:

d-Glutamic acid

DprE1:

Decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase

FtsZ:

Filamenting temperature-sensitive protein Z

GlcB:

Malate synthase

GlcNAc:

N-acetylglucosamine

GyrB:

DNA gyrase subunit B

HTS:

High-throughput screening

l-Ala:

l-Alanine

Ldt:

l,d-transpeptidase

LeuRS:

Leucyl-tRNA synthetase

l-Lys:

l-Lysine

Lpd:

Lipoamide dehydrogenase

MDR:

Multidrug-resistant

MEPS:

Molecular electrostatic potential surface

meso-DAP:

meso-diaminopimelic acid

MIC:

Minimum inhibitory concentration

MSA:

Multiple sequence alignment

Mtb :

Mycobacterium tuberculosis

MurNGlyc:

N-glycolylmuramic acid

NMR:

Nuclear magnetic resonance

PDB:

Protein data bank

PDF:

Peptide deformylase

PG:

Peptidoglycan

PtpA:

Tyrosine phosphatase A

PtpB:

Tyrosine phosphatase B

Qcrb:

Cytochrome bc1 complex

QSAR:

Quantitative structure activity relationship

RNAP:

RNA polymerase enzyme

ROS:

Reactive oxygen species

TB:

Tuberculosis

TCA:

Tricarboxylic acid

VS:

Virtual screening

WHO:

World Health Organization

XDR:

Extensively drug-resistant

References

  1. World Health Organization (2017) Global tuberculosis report 2017

    Google Scholar 

  2. Ducati RG, Ruffino-Netto A, Basso LA, Santos DS (2006) The resumption of consumption: a review on tuberculosis. Memórias do Instituto Oswaldo Cruz 101:697–714

    Article  CAS  PubMed  Google Scholar 

  3. Strebhardt K, Ullrich A (2008) Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer 8:473–480

    Article  CAS  PubMed  Google Scholar 

  4. Bloom BR, Murray CJ (1992) Tuberculosis: commentary on a reemergent killer. Science 257:1055–1064

    Article  CAS  PubMed  Google Scholar 

  5. Zhang Y (2005) The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol 45:529–564

    Article  CAS  PubMed  Google Scholar 

  6. Cole S, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon S, Eiglmeier K, Gas S, Barry Iii C (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544

    Article  CAS  PubMed  Google Scholar 

  7. Chaitanya M, Babajan B, Anuradha C, Naveen M, Rajasekhar C, Madhusudana P, Kumar CS (2010) Exploring the molecular basis for selective binding of Mycobacterium tuberculosis Asp kinase toward its natural substrates and feedback inhibitors: a docking and molecular dynamics study. J Mol Model 16:1357–1367

    Article  CAS  PubMed  Google Scholar 

  8. da Cunha EF, Barbosa EF, Oliveira AA, Ramalho TC (2010) Molecular modeling of Mycobacterium tuberculosis DNA gyrase and its molecular docking study with gatifloxacin inhibitors. J Biomol Struct Dyn 27:619–625

    Article  PubMed  Google Scholar 

  9. Khedkar SA, Malde AK, Coutinho EC, Srivastava S (2007) Pharmacophore modeling in drug discovery and development: an overview. Med Chem 3:187–197

    Article  CAS  PubMed  Google Scholar 

  10. Yuan T, Sampson NS (2018) Hit generation in TB drug discovery: from genome to granuloma. Chem Rev 118:1887–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Brennan PJ, Crick DC (2007) The cell-wall core of Mycobacterium tuberculosis in the context of drug discovery. Curr Top Med Chem 7:475–488

    Article  CAS  PubMed  Google Scholar 

  13. Trefzer C, Škovierová H, Buroni S, Bobovská A, Nenci S, Molteni E, Pojer F, Pasca MR, Makarov V, Cole ST (2011) Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase DprE1. J Am Chem Soc 134:912–915

    Article  PubMed  CAS  Google Scholar 

  14. Mikusova K, Slayden RA, Besra GS, Brennan PJ (1995) Biogenesis of the mycobacterial cell wall and the site of action of ethambutol. Antimicrob Agents Chemother 39:2484–2489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Richter A, Rudolph I, Möllmann U, Voigt K, Chung C-W, Singh OM, Rees M, Mendoza-Losana A, Bates R, Ballell L (2018) Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1. Sci Rep 8:13473

    Article  PubMed  PubMed Central  Google Scholar 

  16. Gao P, Yang Y, Xiao C, Liu Y, Gan M, Guan Y, Hao X, Meng J, Zhou S, Chen X (2012) Identification and validation of a novel lead compound targeting 4-diphosphocytidyl-2-C-methylerythritol synthetase (IspD) of mycobacteria. Eur J Pharmacol 694:45–52

    Article  CAS  PubMed  Google Scholar 

  17. Kantardjieff KA, Kim C-Y, Naranjo C, Waldo GS, Lekin T, Segelke BW, Zemla A, Park MS, Terwilliger TC, Rupp B (2004) Mycobacterium tuberculosis RmlC epimerase (Rv3465): a promising drug-target structure in the rhamnose pathway. Acta Crystallogr D Biol Crystallogr 60:895–902

    Article  PubMed  CAS  Google Scholar 

  18. Björkelid C, Bergfors T, Henriksson LM, Stern AL, Unge T, Mowbray SL, Jones TA (2011) Structural and functional studies of mycobacterial IspD enzymes. Acta Crystallogr D Biol Crystallogr 67:403–414

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Johnsson K, King DS, Schultz PG (1995) Studies on the mechanism of action of isoniazid and ethionamide in the chemotherapy of tuberculosis. J Am Chem Soc 117:5009–5010

    Article  CAS  Google Scholar 

  21. Manjunatha UH, Rao SP, Kondreddi RR, Noble CG, Camacho LR, Tan BH, Ng SH, Ng PS, Ma NL, Lakshminarayana SB (2015) Direct inhibitors of InhA are active against Mycobacterium tuberculosis. Sci Transl Med 7:269ra3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Pan P, Tonge JP (2012) Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds. Curr Topics Med Chem 12:672–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Šink R, Sosič I, Živec M, Fernandez-Menendez R, Turk S, Pajk S, Alvarez-Gomez D, Lopez-Roman EM, Gonzales-Cortez C, Rullas-Triconado J (2014) Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis. J Med Chem 58:613–624

    Article  PubMed  CAS  Google Scholar 

  24. Martínez-Hoyos M, Perez-Herran E, Gulten G, Encinas L, Álvarez-Gómez D, Alvarez E, Ferrer-Bazaga S, García-Pérez A, Ortega F, Angulo-Barturen I (2016) Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 8:291–301

    Article  PubMed  PubMed Central  Google Scholar 

  25. Barkan D, Liu Z, Sacchettini JC, Glickman MS (2009) Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of Mycobacterium tuberculosis. Chem Biol 16:499–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wilson R, Kumar P, Parashar V, Vilchèze C, Veyron-Churlet R, Freundlich JS, Barnes SW, Walker JR, Szymonifka MJ, Marchiano E (2013) Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol 9:499–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, Fischer E, Barnes SW, Walker JR, Alland D, Barry CE (2012) SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother (AAC) 05708-11

    Google Scholar 

  28. Ronning DR, Klabunde T, Besra GS, Vissa VD, Belisle JT, Sacchettini JC (2000) Crystal structure of the secreted form of antigen 85C reveals potential targets for mycobacterial drugs and vaccines. Nat Struct Mol Biol 7:141–146

    Article  CAS  Google Scholar 

  29. Warrier T, Tropis M, Werngren J, Diehl A, Gengenbacher M, Schlegel B, Schade M, Oschkinat H, Daffe M, Hoffner S (2012) Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis. Antimicrob Agents Chemother 1735–1743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kovač A, Wilson RA, Besra GS, Filipič M, Kikelj D, Gobec S (2006) New lipophilic phthalimido-and 3-phenoxybenzyl sulfonates: inhibition of antigen 85C mycolyltransferase activity and cytotoxicity. J Enzyme Inhib Med Chem 21:391–397

    Article  PubMed  CAS  Google Scholar 

  31. Anderson DH, Harth G, Horwitz MA, Eisenberg D (2001) An interfacial mechanism and a class of inhibitors inferred from two crystal structures of the Mycobacterium tuberculosis 30 kda major secretory protein (antigen 85B), a mycolyl transferase1. J Mol Biol 307:671–681

    Article  CAS  PubMed  Google Scholar 

  32. Pawelczyk J, Brzostek A, Kremer L, Dziadek B, Rumijowska-Galewicz A, Fiolka M, Dziadek J (2011) AccD6, a key carboxyltransferase, essential for mycolic acid synthesis in Mycobacterium tuberculosis, is dispensable in a non-pathogenic strain. J Bacteriol JB:05638-11

    Google Scholar 

  33. Reddy MC, Breda A, Bruning JB, Sherekar M, Valluru S, Thurman C, Ehrenfeld H, Sacchettini JC (2014) Structure, activity, and inhibition of the carboxyltransferase β-subunit of acetyl-coa carboxylase (AccD6) from Mycobacterium tuberculosis. Antimicrob Agents Chemother 6122–6132

    Google Scholar 

  34. Boldrin F, Ventura M, Degiacomi G, Ravishankar S, Sala C, Svetlikova Z, Ambady A, Dhar N, Kordulakova J, Zhang M (2014) The phosphatidyl-myo-inositol mannosyltransferase PimA is essential for Mycobacterium tuberculosis growth in vitro and in vivo. J Bacteriol 3441–3451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Arvind A, Jain V, Saravanan P, Mohan CG (2013) Uridine monophosphate kinase as potential target for tuberculosis: from target to lead identification. Interdiscip Sci Comput Life Sci 5:296–311

    Article  CAS  Google Scholar 

  36. Arvind A, Kumar V, Saravanan P, Mohan CG (2012) Homology modeling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis. Interdiscip Sci Comput Life Sci 4:223–238

    Article  CAS  Google Scholar 

  37. Kumar V, Saravanan P, Arvind A, Mohan CG (2011) Identification of hotspot regions of MurB oxidoreductase enzyme using homology modeling, molecular dynamics and molecular docking techniques. J Mol Model 17:939–953

    Article  CAS  PubMed  Google Scholar 

  38. Mansour TS, Caufield CE, Rasmussen B, Chopra R, Krishnamurthy G, Morris KM, Svenson K, Bard J, Smeltzer C, Naughton S (2007) Naphthyl tetronic acids as multi-target inhibitors of bacterial peptidoglycan biosynthesis. ChemMedChem Chem Enabling Drug Discov 2:1414–1417

    CAS  Google Scholar 

  39. Tran AT, 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. Nat Commun 8:14414

    Article  PubMed  PubMed Central  Google Scholar 

  40. Silver LL (2003) Novel inhibitors of bacterial cell wall synthesis. Curr Opin Microbiol 6:431–438

    Article  CAS  PubMed  Google Scholar 

  41. Silver LL (2006) Does the cell wall of bacteria remain a viable source of targets for novel antibiotics? Biochem Pharmacol 71:996–1005

    Article  CAS  PubMed  Google Scholar 

  42. Vollmer W, Blanot D, De Pedro MA (2008) Peptidoglycan structure and architecture. FEMS Microbiol Rev 32:149–167

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gupta R, Lavollay M, Mainardi J-L, Arthur M, Bishai WR, Lamichhane G (2010) The Mycobacterium tuberculosis protein Ldt Mt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nat Med 16:466–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P (2008) The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev 32:234–258

    Article  CAS  PubMed  Google Scholar 

  46. Bianchet MA, Pan YH, Basta LAB, Saavedra H, Lloyd EP, Kumar P, Mattoo R, Townsend CA, Lamichhane G (2017) Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase Ldt Mt2 by biapenem and tebipenem. BMC Biochem 18:8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kim HS, Kim J, Im HN, Yoon JY, An DR, Yoon HJ, Kim JY, Min HK, Kim S-J, Lee JY (2013) Structural basis for the inhibition of Mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains. Acta Crystallogr D Biol Crystallogr 69:420–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chakraborti PK, Matange N, Nandicoori VK, Singh Y, Tyagi JS, Visweswariah SS (2011) Signalling mechanisms in Mycobacteria. Tuberculosis 91:432–440

    Article  CAS  PubMed  Google Scholar 

  49. Park HD, Guinn KM, Harrell MI, Liao R, Voskuil MI, Tompa M, Schoolnik GK, Sherman DR (2003) Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol Microbiol 48:833–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shiloh MU, Manzanillo P, Cox JS (2008) Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection. Cell Host Microbe 3:323–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Taneja NK, Dhingra S, Mittal A, Naresh M, Tyagi JS (2010) Mycobacterium tuberculosis transcriptional adaptation, growth arrest and dormancy phenotype development is triggered by vitamin C. PLoS ONE 5:e10860

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Voskuil MI, Schnappinger D, Visconti KC, Harrell MI, Dolganov GM, Sherman DR, Schoolnik GK (2003) Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 198:705–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kaur K, Taneja NK, Dhingra S, Tyagi JS (2014) DevR (DosR) mimetic peptides impair transcriptional regulation and survival of Mycobacterium tuberculosis under hypoxia by inhibiting the autokinase activity of DevS sensor kinase. BMC Microbiol 14:195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gupta RK, Thakur TS, Desiraju GR, Tyagi JS (2009) Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis. J Med Chem 52:6324–6334

    Article  CAS  PubMed  Google Scholar 

  55. Fernandez P, Saint-Joanis B, Barilone N, Jackson M, Gicquel B, Cole ST, Alzari PM (2006) The Ser/Thr protein kinase PknB is essential for sustaining mycobacterial growth. J Bacteriol 188:7778–7784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lougheed KE, Osborne SA, Saxty B, Whalley D, Chapman T, Bouloc N, Chugh J, Nott TJ, Patel D, Spivey VL (2011) Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents. Tuberculosis 91:277–286

    Article  CAS  PubMed  Google Scholar 

  57. Singh N, Tiwari S, Srivastava KK, Siddiqi MI (2015) Identification of novel inhibitors of Mycobacterium tuberculosis PknG using pharmacophore based virtual screening, docking, molecular dynamics simulation, and their biological evaluation. J Chem Inf Model 55:1120–1129

    Article  CAS  PubMed  Google Scholar 

  58. Chiaradia LD, Mascarello A, Purificação M, Vernal J, Cordeiro MNS, Zenteno ME, Villarino A, Nunes RJ, Yunes RA, Terenzi H (2008) Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg Med Chem Lett 18:6227–6230

    Article  CAS  PubMed  Google Scholar 

  59. Tan LP, Wu H, Yang P-Y, Kalesh KA, Zhang X, Hu M, Srinivasan R, Yao SQ (2009) High-throughput discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitors using click chemistry. Org Lett 11:5102–5105

    Article  CAS  PubMed  Google Scholar 

  60. Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y (2011) Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H + –ATPase to inhibit phagosome acidification. Proc Natl Acad Sci 108:19371–19376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sharma A, Khuller GK, Sharma S (2009) Peptide deformylase–a promising therapeutic target for tuberculosis and antibacterial drug discovery. Expert opinion on therapeutic targets 13:753–765

    Article  CAS  PubMed  Google Scholar 

  62. Serero A, Giglione C, Sardini A, Martinez-Sanz J, Meinnel T (2003) An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway. J Biol Chem 278:52953–52963

    Article  CAS  PubMed  Google Scholar 

  63. Cynamon MH, Alvirez-Freites E, Yeo AE (2004) BB-3497, a peptide deformylase inhibitor, is active against Mycobacterium tuberculosis. J Antimicrob Chemother 53:403–405

    Article  CAS  PubMed  Google Scholar 

  64. Lofland D, Difuntorum S, Waller A, Clements JM, Weaver MK, Karlowsky JA, Johnson K (2004) In vitro antibacterial activity of the peptide deformylase inhibitor BB-83698. J Antimicrob Chemother 53:664–668

    Article  CAS  PubMed  Google Scholar 

  65. Sharma A, Sharma S, Khuller G, Kanwar A (2009) In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv. Int J Antimicrob Agents 34:226–230

    Article  CAS  PubMed  Google Scholar 

  66. Gurcha SS, Usha V, Cox JA, Futterer K, Abrahams KA, Bhatt A, Alderwick LJ, Reynolds RC, Loman NJ, Nataraj V, Alemparte C, Barros D, Lloyd AJ, Ballell L, Hobrath JV, Besra GS (2014) Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target. PLoS ONE 9:e113568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Soto R, Perez-Herran E, Rodriguez B, Duma BM, Cacho-Izquierdo M, Mendoza-Losana A, Lelievre J, Aguirre DB, Ballell L, Cox LR, Alderwick LJ, Besra GS (2018) Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach. Sci Rep 8:12664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Palencia A, Li X, Bu W, Choi W, Ding CZ, Easom EE, Feng L, Hernandez V, Houston P, Liu L (2016) Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase. Antimicrob Agents Chemother 6271–6280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rock FL, Mao W, Yaremchuk A, Tukalo M, Crépin T, Zhou H, Zhang Y-K, Hernandez V, Akama T, Baker SJ (2007) An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316:1759–1761

    Article  CAS  PubMed  Google Scholar 

  70. Abrahams KA, Cox JA, Spivey VL, Loman NJ, Pallen MJ, Constantinidou C, Fernandez R, Alemparte C, Remuinan MJ, Barros D (2012) Identification of novel imidazo [1, 2-a] pyridine inhibitors targeting M. tuberculosis QcrB. PloS one 7:e52951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Moraski GC, Seeger N, Miller PA, Oliver AG, Boshoff HI, Cho S, Mulugeta S, Anderson JR, Franzblau SG, Miller MJ (2016) Arrival of imidazo [2, 1-b] thiazole-5-carboxamides: potent anti-tuberculosis agents that target QcrB. ACS Infect Dis 2:393–398

    Article  CAS  PubMed  Google Scholar 

  72. Chandrasekera NS, Berube BJ, Shetye G, Chettiar S, O’Malley T, Manning A, Flint L, Awasthi D, Ioerger TR, Sacchettini J (2017) Improved phenoxyalkylbenzimidazoles with activity against Mycobacterium tuberculosis appear to target QcrB. ACS Infect Dis 3:898–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. McKinney JD, Zu Bentrup KH, Muñoz-Elías EJ, Miczak A, Chen B, Chan W-T, Swenson D, Sacchettini JC, Jacobs WR Jr, Russell DG (2000) Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:735–738

    Article  CAS  PubMed  Google Scholar 

  74. Muñoz-Elías EJ, McKinney JD (2005) Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11:638–644

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Huang H-L, Krieger IV, Parai MK, Gawandi VB, Sacchettini JC (2016) Mycobacterium tuberculosis malate synthase structures with fragments reveal a portal for substrate/product exchange. J Biol Chem 27421–27432

    Article  CAS  Google Scholar 

  76. Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera J-L (2012) Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase. Chem Biol 19:1556–1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Andries K, Verhasselt P, Guillemont J, Göhlmann HW, Neefs J-M, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E (2005) A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307:223–227

    Article  CAS  PubMed  Google Scholar 

  78. Kundu S, Biukovic G, Grüber G, Dick T (2016) Bedaquiline targets the ϵ subunit of mycobacterial F-ATP synthase. Antimicrob Agents Chemother 6977–6979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S, Jiricek J, Jung J, Jeon HK, Cechetto J (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19:1157–1160

    Article  CAS  PubMed  Google Scholar 

  80. Bryk R, Arango N, Venugopal A, Warren JD, Park Y-H, Patel MS, Lima CD, Nathan C (2010) Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase. Biochemistry 49:1616–1627

    Article  CAS  PubMed  Google Scholar 

  81. Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C (2011) Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe 9:21–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tullius MV, Harth G, Horwitz MA (2003) Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Infect Immun 71:3927–3936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Harth G, Horwitz MA (2003) Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis: demonstration of efficacy in vivo. Infect Immun 71:456–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kasbekar M, Fischer G, Mott BT, Yasgar A, Hyvönen M, Boshoff HI, Abell C, Barry CE, Thomas CJ (2016) Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site. Proc Natl Acad Sci 113:7503–7508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li M, Huang Y-J, Tai PC, Wang B (2008) Discovery of the first SecA inhibitors using structure-based virtual screening. Biochem Biophys Res Commun 368:839–845

    Article  CAS  PubMed  Google Scholar 

  86. Chen W, Huang Y-J, Gundala SR, Yang H, Li M, Tai PC, Wang B (2010) The first low μM SecA inhibitors. Bioorg Med Chem 18:1617–1625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Via LE, Savic R, Weiner DM, Zimmerman MD, Prideaux B, Irwin SM, Lyon E, O’Brien P, Gopal P, Eum S (2015) Host-mediated bioactivation of pyrazinamide: implications for efficacy, resistance, and therapeutic alternatives. ACS Infect Dis 1:203–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z (2003) Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother 52:790–795

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mdluli K, Ma Z (2007) Mycobacterium tuberculosis DNA gyrase as a target for drug discovery. Infect Disorders-Drug Targets (Form Curr Drug Targets-Infect Disorders) 7:159–168

    Article  CAS  Google Scholar 

  91. Onodera Y, Tanaka M, Sato K (2001) Inhibitory activity of quinolones against DNA gyrase of Mycobacterium tuberculosis. J Antimicrob Chemother 47:447–450

    Article  CAS  PubMed  Google Scholar 

  92. Blondeau JM (2004) Fluoroquinolones: mechanism of action, classification, and development of resistance. Surv Ophthalmol 49:S73–S78

    Article  PubMed  Google Scholar 

  93. Piton J, Petrella S, Delarue M, André-Leroux G, Jarlier V, Aubry A, Mayer C (2010) Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase. PLoS ONE 5:e12245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Barancokova M, Kikelj D, Ilas J (2018) Recent progress in the discovery and development of DNA gyrase B inhibitors. Fut Med Chem 10:1207–1227

    Article  CAS  Google Scholar 

  95. Chopra S, Matsuyama K, Tran T, Malerich JP, Wan B, Franzblau SG, Lun S, Guo H, Maiga MC, Bishai WR (2011) Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J Antimicrob Chemother 67:415–421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Shirude PS, Madhavapeddi P, Tucker JA, Murugan K, Patil V, Basavarajappa H, Raichurkar AV, Humnabadkar V, Hussein S, Sharma S, Ramya VK, Narayan CB, Balganesh TS, Sambandamurthy VK (2013) Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis. ACS Chem Biol 8:519–523

    Article  CAS  PubMed  Google Scholar 

  97. Pedgaonkar GS, Sridevi JP, Jeankumar VU, Saxena S, Devi PB, Renuka J, Yogeeswari P, Sriram D (2014) Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA. Bioorg Med Chem 22:6134–6145

    Article  CAS  PubMed  Google Scholar 

  98. Reddy KI, Srihari K, Renuka J, Sree KS, Chuppala A, Jeankumar VU, Sridevi JP, Babu KS, Yogeeswari P, Sriram D (2014) An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition. Bioorg Med Chem 22:6552–6563

    Article  CAS  PubMed  Google Scholar 

  99. Renuka J, Reddy KI, Srihari K, Jeankumar VU, Shravan M, Sridevi JP, Yogeeswari P, Babu KS, Sriram D (2014) Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis. Bioorg Med Chem 22:4924–4934

    Article  CAS  PubMed  Google Scholar 

  100. Davis CK, Nasla K, Anjana A, Rajanikant G (2018) Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays. Silico Pharmacol 6:8

    Article  Google Scholar 

  101. Cavusoglu C, Hilmioglu S, Guneri S, Bilgic A (2002) Characterization of rpoB mutations in rifampin-resistant clinical isolates of Mycobacterium tuberculosis from Turkey by DNA sequencing and line probe assay. J Clin Microbiol 40:4435–4438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lin W, Mandal S, Degen D, Liu Y, Ebright YW, Li S, Feng Y, Zhang Y, Mandal S, Jiang Y (2017) Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition. Mol Cell 66:169–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang Q, Xu Y, Gu Z, Liu N, Jin K, Li Y, Crabbe MJC, Zhong Y (2018) Identification of new antibacterial targets in RNA polymerase of Mycobacterium tuberculosis by detecting positive selection sites. Comput Biol Chem 73:25–30

    Article  CAS  PubMed  Google Scholar 

  104. Kurabachew M, Lu SH, Krastel P, Schmitt EK, Suresh BL, Goh A, Knox JE, Ma NL, Jiricek J, Beer D (2008) Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis. J Antimicrob Chemother 62:713–719

    Article  CAS  PubMed  Google Scholar 

  105. Scharf NT, Molodtsov V, Kontos A, Murakami KS, Garcia GA (2017) Novel chemical scaffolds for inhibition of rifamycin-resistant RNA polymerase discovered from high-throughput screening. SLAS Discov Adv Life Sci R&D 22:287–297

    CAS  Google Scholar 

  106. Hong W, Deng W, Xie J (2013) The structure, function, and regulation of mycobacterium FtsZ. Cell Biochem Biophys 65:97–105

    Article  CAS  PubMed  Google Scholar 

  107. Huang Q, Kirikae F, Kirikae T, Pepe A, Amin A, Respicio L, Slayden RA, Tonge PJ, Ojima I (2006) Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. J Med Chem 49:463–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Das D, Borah M, Singh AK, Das R, Boruah HPD (2015) Molecular docking of phytochemical as Ftsz cell division protein inhibitor in Mycobacterium tuberculosis. Int J Pharm Sci Res 6:463–472

    Google Scholar 

  109. Brötz-Oesterhelt H, Sass P (2014) Bacterial caseinolytic proteases as novel targets for antibacterial treatment. Int J Med Microbiol 304:23–30

    Article  PubMed  CAS  Google Scholar 

  110. Raju RM, Unnikrishnan M, Rubin DH, Krishnamoorthy V, Kandror O, Akopian TN, Goldberg AL, Rubin EJ (2012) Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection. PLoS Pathog 8:e1002511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gavrish E, Sit CS, Cao S, Kandror O, Spoering A, Peoples A, Ling L, Fetterman A, Hughes D, Bissell A (2014) Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. Chem Biol 21:509–518

    Article  CAS  Google Scholar 

  112. Schmitz KR, Carney DW, Sello JK, Sauer RT (2014) Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery. Proc Natl Acad Sci 111:E4587–E4595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Darwin KH, Ehrt S, Gutierrez-Ramos J-C, Weich N, Nathan CF (2003) The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302:1963–1966

    Article  CAS  PubMed  Google Scholar 

  114. Gandotra S, Schnappinger D, Monteleone M, Hillen W, Ehrt S (2007) In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice. Nat Med 13:1515–1520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Debnath J, Siricilla S, Wan B, Crick DC, Lenaerts AJ, Franzblau SG, Kurosu M (2012) Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. J Med Chem 55:3739–3755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dhiman RK, Mahapatra S, Slayden RA, Boyne ME, Lenaerts A, Hinshaw JC, Angala SK, Chatterjee D, Biswas K, Narayanasamy P (2009) Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72:85–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cagan R (2016) Drug screening using model systems: some basics. Dis Models Mech 9:1241–1244

    Article  Google Scholar 

  118. Maitra A, Bates S, Kolvekar T, Devarajan PV, Guzman JD, Bhakta S (2015) Repurposing-a ray of hope in tackling extensively drug resistance in tuberculosis. Int J Infect Dis (IJID) Off Publ Int Soc Infect Dis 32:50–55

    Google Scholar 

  119. Amantea D, Certo M, Bagetta G (2015) Drug repurposing and beyond: the fundamental role of pharmacology. Funct Neurol 30:79–81

    PubMed  PubMed Central  Google Scholar 

  120. Boguski MS, Mandl KD, Sukhatme VP (2009) Drug discovery. Repurposing with a difference. Science 324:1394–1395

    Article  CAS  PubMed  Google Scholar 

  121. Kato S, Moulder SL, Ueno NT, Wheler JJ, Meric-Bernstam F, Kurzrock R, Janku F (2015) Challenges and perspective of drug repurposing strategies in early phase clinical trials. Oncoscience 2:576–580

    Article  PubMed  PubMed Central  Google Scholar 

  122. Napper AD, Mucke HA (2015) A special focus on drug repurposing, rescue, and repositioning. Assay Drug Dev Technol 13:293

    Article  CAS  PubMed  Google Scholar 

  123. Oprea TI, Mestres J (2012) Drug repurposing: far beyond new targets for old drugs. AAPS J 14:759–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Strittmatter SM (2014) Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks. Nat Med 20:590–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Solapure S, Dinesh N, Shandil R, Ramachandran V, Sharma S, Bhattacharjee D, Ganguly S, Reddy J, Ahuja V, Panduga V, Parab M, Vishwas KG, Kumar N, Balganesh M, Balasubramanian V (2013) In vitro and in vivo efficacy of beta-lactams against replicating and slowly growing/nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 57:2506–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Correale S, Ruggiero A, Capparelli R, Pedone E, Berisio R (2013) Structures of free and inhibited forms of the l,d-transpeptidase LdtMt1 from Mycobacterium tuberculosis. Acta Crystallographica Section D 69:1697–1706

    Article  CAS  Google Scholar 

  127. Zheng H, Colvin CJ, Johnson BK, Kirchhoff PD, Wilson M, Jorgensen-Muga K, Larsen SD, Abramovitch RB (2017) Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nat Chem Biol 13:218–225

    Article  CAS  PubMed  Google Scholar 

  128. Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F, Kreiswirth B, Poidinger M, Chee C, Kaplan G, Wang YT, De Libero G (2014) Metformin as adjunct antituberculosis therapy. Sci Transl Med 6:263ra159

    Article  PubMed  CAS  Google Scholar 

  129. Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK (2017) Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis Off Publ Braz Soc Infect Dis 312–316

    Article  PubMed  Google Scholar 

  130. Tyagi S, Ammerman NC, Li SY, Adamson J, Converse PJ, Swanson RV, Almeida DV, Grosset JH (2015) Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. Proc Natl Acad Sci 112:869–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Levy L, Randall HP (1970) A study of skin pigmentation by clofazimine. International journal of leprosy and other mycobacterial diseases: official organ of the International Leprosy Association 38:404–416

    CAS  Google Scholar 

  132. Murashov MD, LaLone V, Rzeczycki PM, Keswani RK, Yoon GS, Sud S, Rajeswaran W, Larsen S, Stringer KA, Rosania GR (2017) The physicochemical basis of clofazimine-induced skin pigmentation. J Invest Dermatol 697–703

    Article  CAS  Google Scholar 

  133. Tanaka E, Kimoto T, Tsuyuguchi K, Watanabe I, Matsumoto H, Niimi A, Suzuki K, Murayama T, Amitani R, Kuze F (1999) Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 160:866–872

    Article  CAS  PubMed  Google Scholar 

  134. Lebel M (1993) Pharmacokinetic properties of clarithromycin: a comparison with erythromycin and azithromycin. Canad J infectious Dis (Journal canadien des maladies infectieuses) 4:148–152

    CAS  Google Scholar 

  135. Cavalieri SJ, Biehle JR, Sanders WE (1995) Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 39:1542–1545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Falzon D, Schünemann HJ, Harausz E, González-Angulo L, Lienhardt C, Jaramillo E, Weyer K (2017) World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur Respir J 49:1602308

    Article  PubMed  PubMed Central  Google Scholar 

  137. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, Odhiambo J, Amukoye E, Bah B, Kassa F (2014) A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med 371:1588–1598

    Article  PubMed  CAS  Google Scholar 

  138. Tang S, Yao L, Hao X, Zhang X, Liu G, Liu X, Wu M, Zen L, Sun H, Liu Y (2014) Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China. Eur Respir J 25–29

    Google Scholar 

  139. Weinstein EA, Yano T, Li L-S, Avarbock D, Avarbock A, Helm D, McColm AA, Duncan K, Lonsdale JT, Rubin H (2005) Inhibitors of type II NADH: menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci 102:4548–4553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Crowle AJ, Douvas GS, May MH (1992) Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy 38:410–419

    Article  CAS  PubMed  Google Scholar 

  141. Hollister LE, Eikenberry DT, Raffel S (1960) Chlorpromazine in nonpsychotic patients with pulmonary tuberculosis. Am Rev Respir Dis 81:562–566

    CAS  PubMed  Google Scholar 

  142. Anquetin G, Greiner J, Mahmoudi N, Santillana-Hayat M, Gozalbes R, Farhati K, Derouin F, Aubry A, Cambau E, Vierling P (2006) Design, synthesis and activity against Toxoplasma gondii, Plasmodium spp., and Mycobacterium tuberculosis of new 6-fluoroquinolones. Eur J Med Chem 41:1478–1493

    Article  CAS  PubMed  Google Scholar 

  143. Mehra R, Rani C, Mahajan P, Vishwakarma RA, Khan IA, Nargotra A (2016) Computationally guided identification of novel Mycobacterium tuberculosis GlmU inhibitory leads, their optimization, and in vitro validation. ACS combinatorial science 18:100–116

    Article  CAS  PubMed  Google Scholar 

  144. Janardhan S, John L, Prasanthi M, Poroikov V, Narahari Sastry G (2017) A QSAR and molecular modelling study towards new lead finding: Polypharmacological approach to Mycobacterium tuberculosis. SAR QSAR Environ Res 28:815–832

    Article  CAS  PubMed  Google Scholar 

  145. Choudhury C, Priyakumar UD, Sastry GN (2015) Dynamics based pharmacophore models for screening potential inhibitors of mycobacterial cyclopropane synthase. J Chem Inf Model 55:848–860

    Article  CAS  PubMed  Google Scholar 

  146. Nandi S, Ahmed S, Saxena A (2018) Combinatorial design and virtual screening of potent anti-tubercular fluoroquinolone and isothiazoloquinolone compounds utilizing QSAR and pharmacophore modelling. SAR QSAR Environ Res 29:151–170

    Article  CAS  PubMed  Google Scholar 

  147. Singh S, Mandal PK, Singh N, Misra AK, Singh S, Chaturvedi V, Sinha S, Saxena AK (2010) Substituted hydrazinecarbothioamide as potent antitubercular agents: synthesis and quantitative structure–activity relationship (QSAR). Bioorg Med Chem Lett 20:2597–2600

    Article  CAS  PubMed  Google Scholar 

  148. Karan S, Kashyap VK, Shafi S, Saxena AK (2017) Structural and inhibition analysis of novel sulfur-rich 2-mercaptobenzothiazole and 1, 2, 3-triazole ligands against Mycobacterium tuberculosis DprE1 enzyme. J Mol Model 23:241

    Article  PubMed  CAS  Google Scholar 

  149. Zhang G, Guo S, Cui H, Qi J (2018) Virtual screening of small molecular inhibitors against DprE1. Molecules 23:524

    Article  PubMed Central  CAS  Google Scholar 

  150. Kandasamy S, Hassan S, Gopalaswamy R, Narayanan S (2014) Homology modelling, docking, pharmacophore and site directed mutagenesis analysis to identify the critical amino acid residue of PknI from Mycobacterium tuberculosis. J Mol Graph Model 52:11–19

    Article  CAS  PubMed  Google Scholar 

  151. Appunni S, Rajisha P, Rubens M, Chandana S, Singh HN, Swarup V (2017) Targeting PknB, an eukaryotic-like serine/threonine protein kinase of Mycobacterium tuberculosis with phytomolecules. Comput Biol Chem 67:200–204

    Article  CAS  PubMed  Google Scholar 

  152. Dkhar HK, Gopalsamy A, Loharch S, Kaur A, Bhutani I, Saminathan K, Bhagyaraj E, Chandra V, Swaminathan K, Agrawal P (2014) Discovery of Mycobacterium tuberculosis-1, 4-glucan branching enzyme (GlgB) inhibitors by structure-and ligand-based virtual screening. J Biol Chem 2015:76–89

    Google Scholar 

  153. Muddassar M, Jang JW, Gon HS, Cho YS, Kim EE, Keum KC, Oh T, Cho S-N, Pae AN (2010) Identification of novel antitubercular compounds through hybrid virtual screening approach. Bioorg Med Chem 18:6914–6921

    Article  CAS  PubMed  Google Scholar 

  154. Naidu KM, Srinivasarao S, Agnieszka N, Ewa A-K, Kumar MMK, Sekhar KVGC (2016) Seeking potent anti-tubercular agents: design, synthesis, anti-tubercular activity and docking study of various ((triazoles/indole)-piperazin-1-yl/1, 4-diazepan-1-yl) benzo [d] isoxazole derivatives. Bioorg Med Chem Lett 26:2245–2250

    Article  CAS  PubMed  Google Scholar 

  155. Prakash O, Ghosh I (2006) Developing an antituberculosis compounds database and data mining in the search of a motif responsible for the activity of a diverse class of antituberculosis agents. J Chem Inf Model 46:17–23

    Article  CAS  PubMed  Google Scholar 

  156. Dalecki AG, Wolschendorf F (2016) Development of a web-based tool for automated processing and cataloging of a unique combinatorial drug screen. J Microbiol Methods 126:30–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sharma A, Dutta P, Sharma M, Rajput NK, Dodiya B, Georrge JJ, Kholia T, Bhardwaj A (2014) BioPhytMol: a drug discovery community resource on anti-mycobacterial phytomolecules and plant extracts. J Cheminform 6:46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lin K, O’Brien KM, Trujillo C, Wang R, Wallach JB, Schnappinger D, Ehrt S (2016) Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense. PLoS Pathog 12:e1005675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Shigyo K, Ocheretina O, Merveille YM, Johnson WD, Pape JW, Nathan CF, Fitzgerald DW (2013) Efficacy of nitazoxanide against clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2834–2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Li X, Hernandez V, Rock FL, Choi W, Mak YS, Mohan M, Mao W, Zhou Y, Easom EE, Plattner JJ (2017) Discovery of a potent and specific M. tuberculosis Leucyl-tRNA synthetase inhibitor:(S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy) benzo [c][1, 2] oxaborol-1 (3 H)-ol (GSK656). J Med Chem 60:8011–8026

    Article  CAS  PubMed  Google Scholar 

  161. Choi Y, Lee SW, Kim A, Jang K, Nam H, Cho YL, Yu K-S, Jang I-J, Chung J-Y (2017) Safety, tolerability and pharmacokinetics of 21 day multiple oral administration of a new oxazolidinone antibiotic, LCB01-0371, in healthy male subjects. J Antimicrob Chemother 73:183–190

    Article  CAS  Google Scholar 

  162. Shoen C, DeStefano M, Hafkin B, Cynamon M (2018) In vitro and in vivo activity of contezolid (MRX-I) against Mycobacterium tuberculosis. Antimicrob Agents Chemother 00493-18

    Google Scholar 

  163. Wallis RS, Jakubiec WM, Kumar V, Silvia AM, Paige D, Dimitrova D, Li X, Ladutko L, Campbell S, Friedland G (2010) Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers. J Infect Dis 202:745–751

    Article  CAS  PubMed  Google Scholar 

  164. Aagaard C, Hoang T, Dietrich J, Cardona P-J, Izzo A, Dolganov G, Schoolnik GK, Cassidy JP, Billeskov R, Andersen P (2011) A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med 17:189–194

    Article  CAS  PubMed  Google Scholar 

  165. Bleicher KH, Böhm H-J, Müller K, Alanine AI (2003) A guide to drug discovery: hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discov 2:369–378

    Article  CAS  PubMed  Google Scholar 

  166. Agatonovic-Kustrin S, Beresford R (2000) Basic concepts of artificial neural network (ANN) modeling and its application in pharmaceutical research. J Pharm Biomed Anal 22:717–727

    Article  CAS  PubMed  Google Scholar 

  167. Cherkasov A, Hilpert K, Jenssen H, Fjell CD, Waldbrook M, Mullaly SC, Volkmer R, Hancock RE (2008) Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs. ACS Chem Biol 4:65–74

    Article  CAS  Google Scholar 

  168. Duch W, Swaminathan K, Meller J (2007) Artificial intelligence approaches for rational drug design and discovery. Curr Pharm Des 13:1497–1508

    Article  CAS  PubMed  Google Scholar 

  169. Martínez-Romero M, Vázquez-Naya JM, Rabunal RJ, Pita-Fernández S, Macenlle R, Castro-Alvariño J, López-Roses L, Ulla LJ, Martinez-Calvo VA, Vázquez S (2010) Artificial intelligence techniques for colorectal cancer drug metabolism: ontologies and complex networks. Curr Drug Metab 11:347–368

    Article  CAS  PubMed  Google Scholar 

  170. Fujiwara T, Kamada M, Okuno Y (2018) Artificial intelligence in drug discovery. Gan to kagaku ryoho Cancer Chemother 45:593–596

    Google Scholar 

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Acknowledgements

The author ACP acknowledges Kerala State Council for Science, Technology & Environment (KSCSTE) for awarding Junior Research Fellowship (Grant No:1132/2013/KSCSTE), India. The authors thank Indian Council for Medical Research (ICMR) and Department of Biotechnology (DBT; BT/PR5659/MED/29/564/2012), Government of India, New Delhi, India, for financial support. We also acknowledge gratefully Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, for the infrastructure support.

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    Anju Choorakottayil Pushkaran, Raja Biswas & C. Gopi Mohan

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Pushkaran, A.C., Biswas, R., Mohan, C.G. (2019). Impact of Target-Based Drug Design in Anti-bacterial Drug Discovery for the Treatment of Tuberculosis. In: Mohan, C. (eds) Structural Bioinformatics: Applications in Preclinical Drug Discovery Process. Challenges and Advances in Computational Chemistry and Physics, vol 27. Springer, Cham. https://doi.org/10.1007/978-3-030-05282-9_10

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