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Novel Tuberculosis Drugs of the 21st Century
N
NO2N O N O
Philip Bentley
October 7, 2009
N
O
OCF3
PA-824
Br NOH
TMC207
Introduction
Tuberculosis (TB)-
“An infectious disease of humans and animals caused by the
tubercle bacillus and characterized by the formation of tubercles on the lungs and other tissues of the body, often tubercles on the lungs and other tissues of the body, often developing long after the initial infection.”
Tubercle bacillus-“A rod- shaped aerobic bacterium (Mycobacterium
tuberculosis) that causes tuberculosis.”
2
Pickett, J.P., et al., Eds. The American Heritage College dictionary, 4th ed.; Houghton Mifflin Company: Boston, MA, 2002; p 1477.
Image taken from: Jabado, N.; Gros, P. Nature 2005, 434, (7034), 709-711.
An Ancient Disease
“Consumption” and “white plague”
“Hippocrates, the ancient Greek physician, noted that ‘phthisis’ (consumption) was the most widespread ‘phthisis’ (consumption) was the most widespread and fatal disease of his time.” (>2,000 yrs ago)
Found in skulls and spines of Egyptian mummies (4,000 yrs old)
3Nobel Prize Website: http://nobelprize.org/educational_games/medicine/tuberculosis/readmore.html (accessed September 15, 2009).
Today
As of March 24, 2009 (World TB Day)
9.27 million NEW cases in 2007
4Donald, P. R.; van Helden, P. D. N. Engl. J. Med. 2009, 360, (23), 2393-2395.
22 Asian and African countries account for 80% of global TB
Cost to diagnose and treat 1.4 million cases
in high burden regions
$16.9 billion
Pathogenesis of TB
Mode of Infection
Ingestion (intestines)Consumption of contaminated milk
Inhalation (lungs)
5
Reddy, C.A. Veterinary Pathogenic Bacteriology, Department of Microbiology & Molecular Genetics: Michigan State University, 2008, pp194.Jabado, N.; Gros, P. Nature 2005, 434, (7034), 709-711.
Inhalation (lungs)Intake of airborne pathogens
Deposited in Lymph nodes
(~2 weeks)
Pathogenesis of TB
Regional Lymph nodes
Bloodstream
A few Days
1-2 weeks
6
Reddy, C.A. Veterinary Pathogenic Bacteriology, Department of Microbiology & Molecular Genetics: Michigan State University, 2008, pp194.Jabado, N.; Gros, P. Nature 2005, 434, (7034), 709-711.
Also, latent forms
(1/3 population)
Throughout Body
Cell-mediated immuneResponse
infection progressesto Tuberculosis
Organism uptakenby activatedmacrophage
Main Challenge
7Image from: http://www3.niaid.nih.gov/topics/tuberculosis/Research/basicResearch/biology_cell.htm
Normal bacteria cell wall TB cell wall
Vs.
Main Challenge
O
(CH2)23CH3
(CH2)17
OH
(CH2)10CH3(CH2)17
Trehalose =
8
Tonge, P. J. Nat. Struct. Mol. Biol. 2000, 7, 94-96.Yuan, Y.; Barry, C. E., III Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 12828-12833.Image from: http://www3.niaid.nih.gov/topics/tuberculosis/Research/basicResearch/biology_cell.htm
TB cell wall
R =
O
(CH2)23CH3
(CH2)17
OH
(CH2)10CH3(CH2)17
O
(CH2)23CH3
(CH2)17
OH
(CH2)10CH3(CH2)17
H3C OCH3
O
(CH2)23CH3
(CH2)17
OH
(CH2)10CH3(CH2)17
H3C O
O
(CH2)23CH3
(CH2)17
OH
(CH2)10CH3(CH2)17
H3C OH
Mycolyl Transfer Mechanism
9Ronning, D. R.; Klabunde, T.; Besra, G. S.; Vissa, V. D.; Belisle, J. T.; Sacchettini, J. C. Nat. Struct.
Biol. 2000, 7, 141-146.
ag85C protein
Strides Towards a Cure
Nobel Prizes Awarded inPhysiology and Medicine
Robert Koch- 1905Discovery of Mycobacterium
Nobel Prize Website: http://nobelprize.org/educational_games/medicine/tuberculosis/readmore.html (accessed September 15, 2009).
Discovery of Mycobacterium
tuberculosis in 1882
Selman Waksman- 1952 Isolated active antibiotic from
Streptomyces griseus in 1943
10
History of Drug Therapy
Alkaline mineral water, mercury, antimony, cod-liver oil, copper salts
Roman physicians recommended Bathing in human urine, eating wolf liver, and drinking elephant blood
Streptomycin (1943)
OH
OHO
HO NO
H3C
HO
NH2
NH2
OHC
11Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
Streptomycin (1943)Intravenous administration
First reported TB resistance (1947)
Para-aminosalicylic acid (1949)Prevented TB resistance
Need for long term use
Streptomycin
OHO
N
HO
O
NH2
NH2O
HO
HO
HONH
CH3
History of Drug Therapy
Isoniazid (1952)Prodrug: Inhibits mycolic acid synthesis
Prevents latent to active TB N
HNO
NH2
Isoniazid
12
Rouche Phamaceuticals in the U.S.: About US. http://www.rocheusa.com/about/history.html (accessed Oct 4, 2009).Timmins, G. S.; Deretic, V. Mol. Microbiol. 2006, 62, 1220-1227.Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
Pyrazinamide (1954)Mechanism of action uncertain
Disrupts plasma membrane?
Disrupts energy metabolism?
History of Drug Therapy
Ethambutol (1962)inhibits the synthesis of arabinogalactan
13
Rifampin (rifampicin) (1965)Inhibits RNA synthesis
Can eliminate dormant bacteria
O
OH
OH
NH
N
OH
O
O
N
O
OH
HO
O
N
O
O
Rifampin
Belanger, A. E.; Besra, G. S.; Ford, M. E.; Mikusova, K.; Belisle, J. T.; Brennan, P. J.; Inamine, J. M. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 11919-11924.Tonge, P. J. Nat. Struct. Mol. Biol. 2000, 7, 94-96.Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
Combination Drug Therapy
Isoniazid and rifampingreatly decrease TB chance of survival
Isoniazid, rifampin, and pyrazinamide (Aventis: Rifater)shortened drug therapy
14Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
Isoniazid, rifampin, pyrazinamide, and ethambutolif resistant to isoniazid
Isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin
if resistant to both isoniazid and rifampin
Summary of the Drug Regime
O
OH
NH
N
OH
O
N
OH
HO
O
O
O
15Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
N
N
O
NH2
Pyrazinamide
OHOO
N
Rifampin
TB in the United States
22000
24000
26000
28000
30000# o
f P
ers
on
s I
nfe
cte
dTB Case Notifications (USA)
16
Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009 (Publication no. WHO/HTM/TB/2009.411.). Geneva: World Health Organization, 2009.Weis, S. E.; Slocum, P. C.; Blais, F. X.; King, B. ; Nunn, M.; Matney, G. B.; Gomez, E.; Foresman, B. H. N. Engl. J. Med. 1994, 330, 17), 1179-1184.
10000
12000
14000
16000
18000
20000
1975 1980 1985 1990 1995 2000 2005 2010
# o
f P
ers
on
s I
nfe
cte
d
Year
Multi Drug Resistance (MDR)
17
Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009 (Publication no. WHO/HTM/TB/2009.411.). Geneva: World Health Organization, 2009.Donald, P. R.; van Helden, P. D. N. Engl. J. Med. 2009, 360, (23), 2393-2395.
Need for 21st Century Drugs
Development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains
(Not a single new compound since 1965)
Help reduce cost of MDR treatment
($15,000 for a 2 year treatment course)
Minimize fatalities
(30 million claimed btw 2000 and 2020)
18Borchardt, J.K. Drug News Perspect. 2002, 15, (8), 535-542.
Drugs with Promising Results
N
NO2N O
O
OCF3
19
PA-824
N
Br NOH
O
TMC207
Clinical Trial Phases
Phase of Clinical Trial
Number ofPatients
What they test
Preclinical N.A.In-vivo (Animal)
and in-vitro
Metabolic and pharmacologic
20
Phase I 20-30Metabolic and pharmacologic
properties
Phase II >100Test drug effectiveness &
Side effects and risks
Phase III 100s-1000sEfficacy, safety, benefit to risk
Gain FDA approval
Phase IV --- Long term effects
National Marrow Donor Program: What is a Clinical Trial? http://www.marrow.org/PATIENT/Undrstnd_Disease_Treat/Undrstnd_Treat_Opt/Lrn_Clinical_Trials/What_is_a_Clinical_Trial/index.html (accessed Oct 1, 2009).
PA- 824
Phase II
No cross-resistance
Potentially inhibits drug-sensitive and drug-resistant strains
N
NO2N O
O
OCF3
resistant strains
In vitro activity against non-replicating TB
Unique mechanism of action
Inhibits TB cell wall mycolic acid synthesis
Pro-drug metabolized by TB
21
Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, (6789), 962-966.
Synthesis of PA- 824
22Baker, W. R.; Cai, S.; Keeler, E. L. 96-US10904, 9701562, 19960625, 1997.
TBAF = N
F
Synthesis of PA- 824
23Baker, W. R.; Cai, S.; Keeler, E. L. 96-US10904, 9701562, 19960625, 1997.
PA- 824: Activity Against MDR TB
Drug Resistance MIC90 (µµµµg/ ml)
[PA-824]
MIC90 (µµµµg/ ml)
[isoniazid]
Drug susceptible strains 0.015 to 0.25 0.03 to 0.06
R 0.03 0.03
I, R 0.03
24
Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, (6789), 962-966.
I, R, E 0.03
I, S, E 0.25
I, R, S, E 0.03
I, R, E, P 0.06
I, S, E, P 0.25
I= isoniazid; R= rifampin; E= ethambutol; S= streptomycin; P= pyrazinamide
Activity Against Non- Replicating TB
4.5
5
5.5
6
Activity on Non-Replicating TBControl PA-824 Isoniazid
Drug anaerobic No drug, aerobic
25
Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, (6789), 962-966.
1
1.5
2
2.5
3
3.5
4
-7 -5 -3 -1 1 3 5 7
Lo
g10
CF
U
Time (days)
0-7 1 2 4 7
PA- 824: Mechanisms of Action
Two suggested mechanisms
Disruption of the mycolic acids of the TB cell envelope
Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), 1449-1458.Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; Niyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906), 1392-1395.
26
Intracellular NO release
via a deazaflavin-dependent nitroreductase (Ddn) and the reduced form of cofactor F420
PA- 824: Mechanisms of Action
2
3
�
�
27
Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), 1449-1458.Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, (6789), 962-966.
2
3
PA- 824: Mechanisms of Action
Activity as a Prodrug
Little mycolic acid repair
28
Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; Niyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906), 1392-1395.
N
NN
O
R
O
Oreduction
H
N
NN
O
R
O
HO
N
NN
O
R
O
HO
N
NN
O
O
O
protonation
4
5
N
NO
NOH
O
hydrolysis
N
NN
OHO
reduction
N
R
N
NO
R
N
O
HO
5a
6a
29
Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; Niyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906), 1392-1395.
N
R
N
NO
R
O
N
O
H
5b
6b
N
R
N
H2NO
R
reduction
5c
6c
PA- 824: Mechanisms of Action
Deazaflavin- dependent nitroreductase (Ddn)
AND
Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; Niyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906), 1392-1395.
30
OPC- 67683
Completed Phase II
No cross-resistance
Inhibits drug-sensitive and drug-resistant strains
Similar mechanism of action to PA- 824
O
OCF3
N
O
O
N
NNO2
31Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11), 2131-2144.
Similar mechanism of action to PA- 824
Inhibits TB cell wall mycolic acid synthesis
Pro-drug metabolized by TB
Decreased time on drug regime
High efficacy in immunocompromised micesuggesting treatment for TB/HIV patients
Synthesis of OPC- 67683
NHN
O2N
Cl
+Et3N, AcOEt,
60-65 oC, 6 h
87%
OO
O
K2CO3, MeOH,r.t., 2 h97%
7 8
NN
O2N
Cl
OOH
O
NO2
NN
O2N
Cl
OHOH
32Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26), 7854-7860.
O
NO2
1.) MsCl, py., <15 oC, 2 h
2.) DBU, AcOEt, r.t., 2 h
(75% for 2 steps)8
9
NN
O2N
Cl
O
Synthesis of OPC- 67683
33Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26), 7854-7860.
Synthesis of OPC- 67683
34Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26), 7854-7860.
TB Strain (MIC90) MIC90 (µµµµg/ml)
rifampin- susceptible (0.288: 24x) 0.01248
isoniazid- susceptible (0.099: 8x) 0.01194
OPC- 67683: Pharmacokinetics
isoniazid- susceptible (0.099: 8x) 0.01194
ethambutol- susceptible (3.636: 303x) 0.01213
streptomycin- susceptible (2.938: 244x) 0.01203
Average (0.012)
35Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11), 2131-2144.
OPC- 67683: Pharmacokinetics
TB Strain (MIC90) MIC90 (µµµµg/ml)
rifampin- susceptible 0.01248
rifampin- resistant 0.01221
isoniazid- susceptible 0.01194isoniazid- susceptible 0.01194
isoniazid- resistant 0.01279
ethambutol- susceptible 0.01213
ethambutol- resistant 0.01341
streptomycin- susceptible 0.01203
streptomycin- resistant 0.0134
36Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11), 2131-2144.
4
5
6
7
CF
U
ORP RIEP
OPC- 67683: Pharmacokinetics
6/6
0
1
2
3
4
0 1 2 3 4 5 6
Lo
g10
CF
U
Time (month)
37Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11), 2131-2144.
6/6
6/6
6/6
6/66/6
6/6
1/6 0/6
1/6 4/5
0/60/6
O= OPC- 67683; R= rifampin; P= pyrazinamide; I= isoniazid; E= ethambutol
# of mice with CFU / total # mice
OPC- 67683: Mechanism of Action
Same Mechanism of action as PA- 824
38
Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), 1449-1458. Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D. N.; Krelswirth, B. N.; Barry, C. E.; Baker, W. R. Nature 2000, 405, (6789), 962-966.
TMC207 (R207910)
Phase II
Unique mechanism of action
Inhibits membrane-bound ATP synthase
Potentially inhibits drug-sensitive and drug-resistant strains
Reduced time to negative sputum culture
39
Diacon, A. H.; Pym, A.; Grobusch, M.; Patientia, R.; Rustomjee, R.; Page-Shipp, L.; Pistorius, C.; Krause, R.; Bogoshi, M.; Churchyard, G.; Venter, A.; Allen, J.; Palomino, J. C.; De Marez, T.; van Heeswijk, R. P. G.; Lounis, N.; Meyvisch, P.; Verbeeck, J.; Parys, W.; de Beule, K.; Andries, K.; McNeeley, D. F. N. Engl. J. Med. 2009, 360, (23), 2397-2405.
Synthesis of TMC207
40Van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.; Poignet, H. J. J.; Decrane, L. F. B.; Vernier, D. F. J.; Odds, F. C. 2004-7026, 2005148581, 20041208, 2005.
Synthesis of TMC207
41Van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.; Poignet, H. J. J.; Decrane, L. F. B.; Vernier, D. F. J.; Odds, F. C. 2004-7026, 2005148581, 20041208, 2005.
4
5
6
7
8
10
CF
U
Untreated (Day 0) 1 month 2 month
TMC207: Pharmacokinetic Studies
T = TMC207
20% 0% 0% 0%0%% of mice culture (-)
after 2 month
0
1
2
3
4
Untreated T R I P
log
10
Monotherapy
42
Ibrahim, M.; Andries, K.; Lounis, N.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris, N. Antimicrob. Agents Chemother. 2007, 51, 1011-1015.Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; Neefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. Science 2005, 307, (5707), 223-227.
T = TMC207R = rifampinI = isoniazidP = pyrazinamide
TMC207: Pharmacokinetic Studies
T = TMC2073
4
5
6
7
8
log
10
CF
U
Untreated (Day 0) 1 month 2 month
20% 100% 30% 20%0% 20% 0% 0%% of mice culture (-)
after 2 month
43
T = TMC207P = pyrazinamideR = rifampinI = isoniazid0
1
2
3log
Two- drug therapy
Ibrahim, M.; Andries, K.; Lounis, N.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris, N. Antimicrob. Agents Chemother. 2007, 51, 1011-1015.Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; Neefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. Science 2005, 307, (5707), 223-227.
TMC207: Pharmacokinetic Studies
T = TMC2073
4
5
6
7
8
log
10
CF
U
Untreated (Day 0) 1 month 2 month
20% 100% 70% 78%0% 20% 0%% of mice culture (-)
after 2 month
44
T = TMC207P = pyrazinamideR = rifampinI = isoniazid0
1
2
3log
Three- drug therapy
Ibrahim, M.; Andries, K.; Lounis, N.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris, N. Antimicrob. Agents Chemother. 2007, 51, 1011-1015.Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; Neefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. Science 2005, 307, (5707), 223-227.
Phase II Key Findings
TMC207 (N) Placebo (N)
Median Log10 CFU Count(Week 1)
4.7 (8) 5.2 (13)
(Week 2) 1.8 (9) 3.5 (11)
(Week 4) ~0 (6) 2.6 (12)
(Week 6) ~0 (5) 2.2 (11)
45
Diacon, A. H.; Pym, A.; Grobusch, M.; Patientia, R.; Rustomjee, R.; Page-Shipp, L.; Pistorius, C.; Krause, R.; Bogoshi, M.; Churchyard, G.; Venter, A.; Allen, J.; Palomino, J. C.; De Marez, T.; van Heeswijk, R. P. G.; Lounis, N.; Meyvisch, P.; Verbeeck, J.; Parys, W.; de Beule, K.; Andries, K.; McNeeley, D. F. N. Engl. J. Med. 2009, 360, (23), 2397-2405.
(Week 6) ~0 (5) 2.2 (11)
(Week 8) ~0 (7) ~0 (7)
Side Effects
(Nausea)26% (23) 4% (24)
(+) to (-) culture in 8 weeks
48% (23)[10:21]
9% (24)[2:23]
TMC207: Mechanism of Action
H2N
H
Arg-186
a-subunit
46Image taken from: http://www.biologie.uni-hamburg.de/b-online/e19/19d.htm.
O
O
H
Glu-61
c-subunit
Inhibition of c-subunit of ATP synthase
TMC207: Mechanism of Action
47de Jonge, M. R.; Koymans, L. H. M.; Guillemont, J. E. G.; Koul, A.; Andries, K. Proteins: Struct.
Funct. Bioinf. 2007, 67, (4), 971-980.
PA- 824 Activity against non-replicating
OPC-67683High efficacy in immunocompromised
In Summary
High efficacy in immunocompromised
TMC207Increased potency against multidrug resistant strains
All of the AboveActivity against drug-susceptible and resistant stains
48
Although excellent promise,
If used incorrectly, resistance will develop
Understanding disease evolution
The Take Home Message
Better approach to treating a target disease
49
Acknowledgements
Prof. Xuefei Huang
Prof. Babak Borhan
Group Members
Bo, Gopi, Mohammad, Dino, Gilbert, Hovig, Vivian
Medha, Ashley, Dennis, Steve
50
Go State!
51
26 - 20Image from: http://scores.espn.go.com/ncf/photos?photoId=2347018&gameId=29276012713