44. Sambandamurthy VK, Wang X, Chen B, Russell RG, Derrick S, Collins FM, Morris SL,
Jacobs WR Jr (2002) A pantothenate auxotroph of Mycobacterium tuberculosis is highly
attenuated and protects mice against tuberculosis. Nat Med 8(10):1171–1174. https://doi.
org/10.1038/nm765
45. Gold B, Deng H, Bryk R, Vargas D, Eliezer D,
Roberts J, Jiang X, Nathan C (2008) Identification of a copper-binding metallothionein in
pathogenic mycobacteria. Nat Chem Biol 4
(10):609–616.
https://doi.org/10.1038/
nchembio.109
46. Shi X, Festa RA, Ioerger TR, Butler-Wu S, Sacchettini JC, Darwin KH, Samanovic MI (2014)
The copper-responsive RicR regulon contributes to Mycobacterium tuberculosis virulence.
mBio 5(1). https://doi.org/10.1128/mBio.
00876-13
47. Ng VH, Cox JS, Sousa AO, MacMicking JD,
McKinney JD (2004) Role of KatG catalaseperoxidase in mycobacterial pathogenesis:
countering the phagocyte oxidative burst.
Mol Microbiol 52(5):1291–1302. https://
doi.org/10.1111/j.1365-2958.2004.
04078.x
48. Shiloh MU, Manzanillo P, Cox JS (2008)
Mycobacterium tuberculosis senses hostderived carbon monoxide during macrophage
infection. Cell Host Microbe 3(5):323–330.
https://doi.org/10.1016/j.chom.2008.03.
007
49. Gold B, Pingle M, Brickner SJ, Shah N,
Roberts J, Rundell M, Bracken WC,
Warrier T, Somersan S, Venugopal A,
Darby C, Jiang X, Warren JD, Fernandez J,
Ouerfelli O, Nuermberger EL, CunninghamBussel A, Rath P, Chidawanyika T, Deng H,
Realubit R, Glickman JF, Nathan CF (2012)
Nonsteroidal anti-inflammatory drug sensitizes
Mycobacterium tuberculosis to endogenous and
exogenous antimicrobials. Proc Natl Acad Sci
U S A 109(40):16004–16011. https://doi.
org/10.1073/pnas.1214188109
50. Gold B, Smith R, Nguyen Q, Roberts J,
Ling Y, Lopez Quezada L, Somersan S,
Warrier T, Little D, Pingle M, Zhang D,
Ballinger E, Zimmerman M, Dartois V,
Hanson P, Mitscher LA, Porubsky P,
Rogers S, Schoenen FJ, Nathan C, Aube J
(2016) Novel cephalosporins selectively active
on nonreplicating Mycobacterium tuberculosis. J
Med Chem 59(13):6027–6044. https://doi.
org/10.1021/acs.jmedchem.5b01833
51. Warrier T, Martinez-Hoyos M, Marin-AmievaM, Colmenarejo G, Porras-De Francisco E,
Alvarez-Pedraglio AI, Fraile-Gabaldon MT,
Torres-Gomez PA, Lopez-Quezada L,
Gold B, Roberts J, Ling Y, SomersanKarakaya S, Little D, Cammack N, Nathan C,
Mendoza-Losana A (2015) Identification of
novel anti-mycobacterial compounds by
screening a pharmaceutical small-molecule
library against nonreplicating Mycobacterium
tuberculosis. ACS Infect Dis 1(12):580–585.
https://doi.org/10.1021/acsinfecdis.
5b00025
52. Schnappinger D, Ehrt S, Voskuil MI, Liu Y,
Mangan JA, Monahan IM, Dolganov G,
Efron B, Butcher PD, Nathan C, Schoolnik
GK (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages:
insights into the phagosomal environment. J
Exp Med 198(5):693–704. https://doi.org/
10.1084/jem.20030846
53. Zheng P, Somersan-Karakaya S, Lu S,
Roberts J, Pingle M, Warrier T, Little D,
Guo X, Brickner SJ, Nathan CF, Gold B, Liu
G (2014) Synthetic calanolides with bactericidal activity against replicating and nonreplicating Mycobacterium tuberculosis. J Med
Chem 57(9):3755–3772. https://doi.org/10.
1021/jm4019228
54. Saito K, Warrier T, Somersan-Karakaya S,
Kaminski L, Mi J, Jiang X, Park S, Shigyo K,
Gold B, Roberts J, Weber E, Jacobs WR Jr,
Nathan CF (2017) Rifamycin action on RNA
polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A 114
(24):E4832–E4840.
https://doi.org/10.
1073/pnas.1705385114
55. Chengalroyen MD, Beukes GM, Gordhan BG,
Streicher EM, Churchyard G, Hafner R,
Warren R, Otwombe K, Martinson N, Kana
BD (2016) Detection and quantification of
differentially culturable tubercle bacteria in
sputum from patients with tuberculosis. Am J
Respir Crit Care Med 194(12):1532–1540.
https://doi.org/10.1164/rccm.2016040769OC
56. Collins L, Franzblau SG (1997) Microplate
alamar blue assay versus BACTEC 460 system
for high-throughput screening of compounds
against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41(5):1004–1009
57. Franzblau SG, DeGroote MA, Cho SH,
Andries K, Nuermberger E, Orme IM,
Mdluli K, Angulo-Barturen I, Dick T,
Dartois V, Lenaerts AJ (2012) Comprehensive
analysis of methods used for the evaluation of
compounds against Mycobacterium tuberculosis. Tuberculosis (Edinb) 92(6):453–488.
https://doi.org/10.1016/j.tube.2012.07.
003
Multi-stress Model for Nonreplicating M. tuberculosis
635
Jacobs WR Jr (2002) A pantothenate auxotroph of Mycobacterium tuberculosis is highly
attenuated and protects mice against tuberculosis. Nat Med 8(10):1171–1174. https://doi.
org/10.1038/nm765
45. Gold B, Deng H, Bryk R, Vargas D, Eliezer D,
Roberts J, Jiang X, Nathan C (2008) Identification of a copper-binding metallothionein in
pathogenic mycobacteria. Nat Chem Biol 4
(10):609–616.
https://doi.org/10.1038/
nchembio.109
46. Shi X, Festa RA, Ioerger TR, Butler-Wu S, Sacchettini JC, Darwin KH, Samanovic MI (2014)
The copper-responsive RicR regulon contributes to Mycobacterium tuberculosis virulence.
mBio 5(1). https://doi.org/10.1128/mBio.
00876-13
47. Ng VH, Cox JS, Sousa AO, MacMicking JD,
McKinney JD (2004) Role of KatG catalaseperoxidase in mycobacterial pathogenesis:
countering the phagocyte oxidative burst.
Mol Microbiol 52(5):1291–1302. https://
doi.org/10.1111/j.1365-2958.2004.
04078.x
48. Shiloh MU, Manzanillo P, Cox JS (2008)
Mycobacterium tuberculosis senses hostderived carbon monoxide during macrophage
infection. Cell Host Microbe 3(5):323–330.
https://doi.org/10.1016/j.chom.2008.03.
007
49. Gold B, Pingle M, Brickner SJ, Shah N,
Roberts J, Rundell M, Bracken WC,
Warrier T, Somersan S, Venugopal A,
Darby C, Jiang X, Warren JD, Fernandez J,
Ouerfelli O, Nuermberger EL, CunninghamBussel A, Rath P, Chidawanyika T, Deng H,
Realubit R, Glickman JF, Nathan CF (2012)
Nonsteroidal anti-inflammatory drug sensitizes
Mycobacterium tuberculosis to endogenous and
exogenous antimicrobials. Proc Natl Acad Sci
U S A 109(40):16004–16011. https://doi.
org/10.1073/pnas.1214188109
50. Gold B, Smith R, Nguyen Q, Roberts J,
Ling Y, Lopez Quezada L, Somersan S,
Warrier T, Little D, Pingle M, Zhang D,
Ballinger E, Zimmerman M, Dartois V,
Hanson P, Mitscher LA, Porubsky P,
Rogers S, Schoenen FJ, Nathan C, Aube J
(2016) Novel cephalosporins selectively active
on nonreplicating Mycobacterium tuberculosis. J
Med Chem 59(13):6027–6044. https://doi.
org/10.1021/acs.jmedchem.5b01833
51. Warrier T, Martinez-Hoyos M, Marin-AmievaM, Colmenarejo G, Porras-De Francisco E,
Alvarez-Pedraglio AI, Fraile-Gabaldon MT,
Torres-Gomez PA, Lopez-Quezada L,
Gold B, Roberts J, Ling Y, SomersanKarakaya S, Little D, Cammack N, Nathan C,
Mendoza-Losana A (2015) Identification of
novel anti-mycobacterial compounds by
screening a pharmaceutical small-molecule
library against nonreplicating Mycobacterium
tuberculosis. ACS Infect Dis 1(12):580–585.
https://doi.org/10.1021/acsinfecdis.
5b00025
52. Schnappinger D, Ehrt S, Voskuil MI, Liu Y,
Mangan JA, Monahan IM, Dolganov G,
Efron B, Butcher PD, Nathan C, Schoolnik
GK (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages:
insights into the phagosomal environment. J
Exp Med 198(5):693–704. https://doi.org/
10.1084/jem.20030846
53. Zheng P, Somersan-Karakaya S, Lu S,
Roberts J, Pingle M, Warrier T, Little D,
Guo X, Brickner SJ, Nathan CF, Gold B, Liu
G (2014) Synthetic calanolides with bactericidal activity against replicating and nonreplicating Mycobacterium tuberculosis. J Med
Chem 57(9):3755–3772. https://doi.org/10.
1021/jm4019228
54. Saito K, Warrier T, Somersan-Karakaya S,
Kaminski L, Mi J, Jiang X, Park S, Shigyo K,
Gold B, Roberts J, Weber E, Jacobs WR Jr,
Nathan CF (2017) Rifamycin action on RNA
polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A 114
(24):E4832–E4840.
https://doi.org/10.
1073/pnas.1705385114
55. Chengalroyen MD, Beukes GM, Gordhan BG,
Streicher EM, Churchyard G, Hafner R,
Warren R, Otwombe K, Martinson N, Kana
BD (2016) Detection and quantification of
differentially culturable tubercle bacteria in
sputum from patients with tuberculosis. Am J
Respir Crit Care Med 194(12):1532–1540.
https://doi.org/10.1164/rccm.2016040769OC
56. Collins L, Franzblau SG (1997) Microplate
alamar blue assay versus BACTEC 460 system
for high-throughput screening of compounds
against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41(5):1004–1009
57. Franzblau SG, DeGroote MA, Cho SH,
Andries K, Nuermberger E, Orme IM,
Mdluli K, Angulo-Barturen I, Dick T,
Dartois V, Lenaerts AJ (2012) Comprehensive
analysis of methods used for the evaluation of
compounds against Mycobacterium tuberculosis. Tuberculosis (Edinb) 92(6):453–488.
https://doi.org/10.1016/j.tube.2012.07.
003
Multi-stress Model for Nonreplicating M. tuberculosis
635