title: The tuberculosis drug discovery and development pipeline and emerging drug targets.
abstract: The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.
authors: Global Alliance for TB Drug Development, New York, New York 10005.
authors: Khisimuzi
authors: K
authors: Mdluli
authors: Global Alliance for TB Drug Development, New York, New York 10005.
authors: Takushi
authors: T
authors: Kaneko
authors: Global Alliance for TB Drug Development, New York, New York 10005.
authors: Anna
authors: A
authors: Upton
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001688:Biological Products / Q000627:therapeutic use; D002244:Carbon / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001688:Biological Products; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002244:Carbon; D000255:Adenosine Triphosphate; D002784:Cholesterol; D007501:Iron; D010447:Peptide Hydrolases
references: PLoS One. 2013 Nov 07;8(11):e72786
references: 24244263
references: J Chem Inf Comput Sci. 2003 Jan-Feb;43(1):218-27
references: 12546556
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Dec 1;66(Pt 12):1657-61
references: 21139218
references: PLoS Pathog. 2012 Sep;8(9):e1002946
references: 23028335
references: Tuberculosis (Edinb). 2009 Jan;89(1):84-90
references: 18851927
references: J Biol Chem. 2013 Oct 18;288(42):30309-30319
references: 23986448
references: PLoS Pathog. 2011 Sep;7(9):e1002264
references: 21980288
references: Future Med Chem. 2010 Aug;2(8):1283-93
references: 21426019
references: Mol Microbiol. 2003 Apr;48(1):77-84
references: 12657046
references: Tuberculosis (Edinb). 2013 Nov;93(6):569-88
references: 24119636
references: Can J Microbiol. 2014 Mar;60(3):147-54
references: 24588388
references: J Biol Chem. 2010 Jul 16;285(29):22264-75
references: 20448045
references: Nat Med. 2005 Jun;11(6):638-44
references: 15895072
references: J Bacteriol. 2005 Sep;187(18):6300-8
references: 16159762
references: Mol Microbiol. 2005 Aug;57(3):859-68
references: 16045627
references: Antimicrob Agents Chemother. 2012 Jan;56(1):324-31
references: 22024828
references: Infect Immun. 2005 Apr;73(4):2533-40
references: 15784600
references: Chemistry. 2007;13(20):5822-32
references: 17506044
references: J Bacteriol. 2011 Mar;193(6):1473-6
references: 21257778
references: PLoS One. 2008 Jan 30;3(1):e1502
references: 18231589
references: Cell Host Microbe. 2011 Jan 20;9(1):21-31
references: 21238944
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14321-6
references: 14623960
references: J Bacteriol. 2009 Aug;191(16):5232-9
references: 19542286
references: Nature. 1999 Nov 4;402(6757):79-83
references: 10573420
references: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references: 17159923
references: J Biol Chem. 2008 Sep 12;283(37):25273-25280
references: 18625705
references: J Med Chem. 2013 Nov 14;56(21):8849-59
references: 24090347
references: J Antibiot (Tokyo). 2007 Jun;60(6):357-63
references: 17617692
references: Bioorg Med Chem. 2012 May 15;20(10):3255-62
references: 22522007
references: Sci Transl Med. 2013 Dec 4;5(214):214ra168
references: 24307692
references: Structure. 2005 Jan;13(1):29-41
references: 15642259
references: Bioorg Med Chem Lett. 2010 Jun 15;20(12):3658-63
references: 20483615
references: J Bacteriol. 2006 Jan;188(2):424-30
references: 16385031
references: Tuberculosis (Edinb). 2009 Sep;89(5):354-63
references: 19783214
references: PLoS One. 2012;7(12):e52951
references: 23300833
references: Emerg Infect Dis. 1999 May-Jun;5(3):346-52
references: 10341171
references: J Nat Prod. 2012 Mar 23;75(3):311-35
references: 22316239
references: Trends Microbiol. 2011 Jul;19(7):307-14
references: 21561773
references: Chem Biol. 2014 Apr 24;21(4):509-518
references: 24684906
references: J Antimicrob Chemother. 1996 Dec;38(6):1049-53
references: 9023652
references: Trends Microbiol. 2006 Jul;14(7):320-7
references: 16759864
references: Science. 2013 Mar 8;339(6124):1213-6
references: 23471410
references: Angew Chem Int Ed Engl. 2011 Jun 20;50(26):5889-91
references: 21563281
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12989-94
references: 14569030
references: mBio. 2013 Sep 17;4(5):e00475-13
references: 24045640
references: Int J Antimicrob Agents. 2000 Sep;16(1):69-71
references: 11185417
references: ACS Chem Biol. 2012 Aug 17;7(8):1377-84
references: 22577943
references: J Bacteriol. 1999 Dec;181(23):7161-7
references: 10572116
references: J Biol Chem. 2011 Mar 25;286(12):10276-87
references: 21193400
references: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12147-52
references: 22778419
references: J Biol Chem. 2010 Jan 1;285(1):434-43
references: 19875455
references: Curr Med Chem. 2012;19(36):6126-37
references: 23092127
references: Science. 2000 Jun 2;288(5471):1647-50
references: 10834844
references: Mol Microbiol. 2006 Aug;61(4):940-7
references: 16879647
references: PLoS One. 2010 Jul 16;5(7):e11622
references: 20661284
references: Nat Med. 2014 Jan;20(1):75-9
references: 24336248
references: Angew Chem Int Ed Engl. 2009;48(45):8452-6
references: 19780086
references: J Med Microbiol. 2008 Feb;57(Pt 2):164-170
references: 18201981
references: J Med Chem. 2014 Apr 10;57(7):3126-39
references: 24568559
references: J Am Chem Soc. 2006 Jun 14;128(23):7486-91
references: 16756302
references: J Bacteriol. 2012 Feb;194(3):663-8
references: 22123255
references: J Antibiot (Tokyo). 2007 Dec;60(12):733-8
references: 18276996
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 May 1;64(Pt 5):398-401
references: 18453710
references: Hepatology. 2013 Jul;58(1):388-96
references: 23258593
references: EMBO Mol Med. 2009 Apr;1(1):37-49
references: 20049702
references: Acta Crystallogr D Biol Crystallogr. 2007 Feb;63(Pt 2):249-59
references: 17242518
references: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1947-52
references: 17264217
references: J Biol Chem. 2011 Nov 25;286(47):40717-24
references: 21987574
references: Curr Top Microbiol Immunol. 2013;374:135-61
references: 23793585
references: Nat Struct Biol. 2000 Aug;7(8):663-8
references: 10932251
references: Nat Med. 2005 Oct;11(10):1082-7
references: 16200071
references: J Biol Chem. 2012 Nov 9;287(46):38434-41
references: 23002234
references: Drug News Perspect. 2010 Dec;23(10):619-24
references: 21180647
references: Microbiology (Reading). 2003 Jul;149(Pt 7):1829-1835
references: 12855734
references: Nat Chem Biol. 2014 Feb;10(2):96-8
references: 24292073
references: Science. 2005 Jan 14;307(5707):223-7
references: 15591164
references: J Nat Prod. 2011 May 27;74(5):1318-22
references: 21469696
references: PLoS One. 2013 Sep 23;8(9):e75245
references: 24086479
references: Methods Mol Biol. 2012;841:291-319
references: 22222458
references: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8327-32
references: 15928073
references: Chembiochem. 2012 Jan 2;13(1):129-36
references: 22109989
references: ACS Chem Biol. 2012 Jul 20;7(7):1190-7
references: 22500615
references: J Med Chem. 2008 Sep 11;51(17):5349-70
references: 18690677
references: Assay Drug Dev Technol. 2011 Jun;9(3):299-310
references: 21281130
references: PLoS Pathog. 2009 Mar;5(3):e1000344
references: 19300498
references: PLoS One. 2013 Jul 30;8(7):e68942
references: 23935911
references: J Bacteriol. 2001 Dec;183(24):7076-86
references: 11717265
references: Mol Microbiol. 2006 Jun;60(5):1109-22
references: 16689789
references: ACS Med Chem Lett. 2011 Nov 10;2(11):818-823
references: 22267981
references: Antimicrob Agents Chemother. 2012 Jan;56(1):446-57
references: 21986820
references: J Med Chem. 2007 Aug 23;50(17):3973-5
references: 17658779
references: Science. 2008 Nov 28;322(5906):1392-5
references: 19039139
references: PLoS Pathog. 2011 Oct;7(10):e1002287
references: 21998585
references: Curr Opin Microbiol. 2009 Oct;12(5):482-9
references: 19647477
references: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4548-53
references: 15767566
references: Biol Pharm Bull. 2011;34(8):1287-90
references: 21804219
references: Bioorg Med Chem Lett. 2013 Sep 1;23(17):4996-5001
references: 23867166
references: J Bacteriol. 2011 Apr;193(7):1767-70
references: 21296960
references: J Biol Chem. 2003 Jan 17;278(3):1735-43
references: 12393860
references: Med Chem. 2009 Mar;5(2):197-207
references: 19275719
references: Ann Rheum Dis. 2004 Nov;63 Suppl 2:ii50-ii56
references: 15479872
references: J Med Chem. 2014 Feb 27;57(4):1276-88
references: 24450589
references: J Immunol. 2000 Nov 1;165(9):5186-91
references: 11046051
references: Curr Top Med Chem. 2012;12(7):735-65
references: 22283816
references: Microbiol Mol Biol Rev. 2000 Dec;64(4):672-93
references: 11104814
references: J Biol Chem. 2013 Jul 26;288(30):21714-28
references: 23760277
references: Science. 2002 Feb 8;295(5557):1073-7
references: 11799204
references: Nat Chem Biol. 2012 Feb 19;8(4):334-41
references: 22344175
references: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11945-50
references: 18697942
references: Infect Immun. 2006 Jan;74(1):56-63
references: 16368957
references: Microbiology (Reading). 2010 Nov;156(Pt 11):3445-3455
references: 20688819
references: Bioorg Med Chem Lett. 2014 Jan 15;24(2):413-8
references: 24388805
references: EMBO Mol Med. 2012 Oct;4(10):1032-42
references: 22987724
references: Chem Biol. 2012 Dec 21;19(12):1556-67
references: 23261599
references: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7534-9
references: 11416222
references: ACS Med Chem Lett. 2013 Apr 01;4(5):451-5
references: 24900693
references: J Med Chem. 2012 Apr 26;55(8):3739-55
references: 22449052
references: J Biol Chem. 2001 May 11;276(19):16137-45
references: 11278451
references: PLoS Pathog. 2005 Sep;1(1):e2
references: 16201014
references: Nature. 1998 Jun 11;393(6685):537-44
references: 9634230
references: Cell Host Microbe. 2008 Mar 13;3(3):137-45
references: 18329613
references: Nature. 2000 Sep 14;407(6801):211-5
references: 11001062
references: J Biol Chem. 2008 Jun 27;283(26):17827-37
references: 18434314
references: PLoS Pathog. 2011 Sep;7(9):e1002251
references: 21980284
references: J Antimicrob Chemother. 2013 Apr;68(4):869-80
references: 23228936
references: Science. 2009 Jul 10;325(5937):161-5
references: 19589993
references: Infect Immun. 2010 Jan;78(1):275-82
references: 19822655
references: J Microbiol Methods. 2013 Aug;94(2):152-158
references: 23747411
references: ACS Med Chem Lett. 2011 Jun 9;2(6):466-470
references: 21691438
references: Biochemistry. 2010 Mar 2;49(8):1616-27
references: 20078138
references: Microb Pathog. 2000 Jun;28(6):335-42
references: 10839970
references: Front Biosci (Landmark Ed). 2012 Jan 01;17(5):1861-81
references: 22201841
references: Microbiology (Reading). 2002 Oct;148(Pt 10):2975-2986
references: 12368431
references: Expert Rev Anti Infect Ther. 2011 Aug;9(8):589-613
references: 21819327
references: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4176-81
references: 21368134
references: J Nutr. 2007 May;137(5):1341-4
references: 17449603
references: ChemMedChem. 2013 Feb;8(2):313-21
references: 23307663
references: J Med Chem. 2013 Mar 14;56(5):1789-95
references: 23356819
references: Indian J Exp Biol. 2009 Jun;47(6):407-11
references: 19634704
references: J Exp Med. 2003 Sep 1;198(5):693-704
references: 12953091
references: J Bacteriol. 2012 Feb;194(3):567-75
references: 22101841
references: Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11565-70
references: 23798446
references: Nature. 2000 Aug 17;406(6797):735-8
references: 10963599
references: Infect Immun. 2008 Jun;76(6):2333-40
references: 18347040
references: J Biol Chem. 2008 Dec 19;283(51):35368-74
references: 18955493
references: Bioorg Med Chem Lett. 2013 Nov 15;23(22):6052-9
references: 24103299
references: Pharmaceuticals (Basel). 2012 Nov 09;5(11):1210-35
references: 24281307
references: Annu Rev Microbiol. 2000;54:881-941
references: 11018148
references: EMBO Mol Med. 2010 Jul;2(7):258-74
references: 20597103
references: PLoS Pathog. 2013 Jan;9(1):e1003120
references: 23431276
references: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9819-24
references: 20439709
references: N Engl J Med. 2009 Jun 4;360(23):2397-405
references: 19494215
references: PLoS Pathog. 2011 Jul;7(7):e1002091
references: 21814509
references: J Org Chem. 2013 Aug 2;78(15):7470-81
references: 23805993
references: Eur J Med Chem. 2012 Mar;49:1-23
references: 22280816
references: Int J Mol Sci. 2013 Apr 17;14(4):8491-5
references: 23594999
references: Chem Biol. 2010 Oct 29;17(10):1122-31
references: 21035735
references: Toxicol Sci. 2013 Jan;131(1):271-8
references: 22977170
references: Bioorg Med Chem. 2011 Sep 15;19(18):5585-95
references: 21840723
references: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4376-80
references: 18334639
references: Mol Microbiol. 2009 Apr;72(1):85-97
references: 19220750
references: J Med Chem. 2013 Nov 14;56(21):8533-42
references: 24107081
references: Bioorg Med Chem. 2012 Apr 1;20(7):2214-20
references: 22391032
references: PLoS Pathog. 2013 Jan;9(1):e1003116
references: 23326232
references: Antimicrob Agents Chemother. 2012 Apr;56(4):1797-809
references: 22252828
references: Mol Microbiol. 2013 Feb;87(4):744-55
references: 23240649
references: Microbiol Rev. 1996 Dec;60(4):575-608
references: 8987357
references: Tuberculosis (Edinb). 2009 Sep;89(5):334-53
references: 19758845
references: Bioorg Med Chem Lett. 2013 Sep 1;23(17):4741-50
references: 23910985
references: Chem Biol. 2012 Jul 27;19(7):844-54
references: 22840772
references: Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):12984-9
references: 23872845
references: PLoS One. 2013 Apr 17;8(4):e60933
references: 23613759
references: PLoS One. 2009 Dec 24;4(12):e8448
references: 20041149
references: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11354-9
references: 22733761
references: J Antimicrob Chemother. 2003 Nov;52(5):790-5
references: 14563891
references: J Biol Chem. 2004 May 14;279(20):21257-65
references: 15001577
references: Infect Immun. 2012 Oct;80(10):3650-9
references: 22802345
references: J Biol Chem. 2011 Dec 23;286(51):43668-43678
references: 22045806
references: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6554-9
references: 23576728
references: Infect Immun. 2005 Jun;73(6):3492-501
references: 15908378
references: Nat Med. 2013 Sep;19(9):1157-60
references: 23913123
references: J Infect Dis. 2007 Sep 1;196(5):788-95
references: 17674323
references: Mol Microbiol. 2013 Jan;87(2):269-83
references: 23146019
references: Expert Opin Drug Discov. 2013 May;8(5):479-93
references: 23480029
references: Infect Disord Drug Targets. 2007 Sep;7(3):213-20
references: 17897057
references: Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1945-50
references: 24497493
references: ACS Chem Biol. 2013 Dec 20;8(12):2669-77
references: 24047344
references: Microbes Infect. 2012 Mar;14(3):207-16
references: 22033148
references: Tuberculosis (Edinb). 2014 Jan;94(1):8-14
references: 24157189
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18792-7
references: 19846780
references: Nature. 2013 Nov 21;503(7476):365-70
references: 24226776
references: Microbiology (Reading). 2010 Jan;156(Pt 1):81-87
references: 19797356
references: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5051-6
references: 21383189
references: Curr Top Med Chem. 2012;12(7):672-93
references: 22283812
references: J Infect Dis. 2013 Oct 15;208(8):1255-65
references: 23788726