Novel Inhibitors of Cholesterol Degradation in Mycobacterium tuberculosis Reveal How the Bacterium’s Metabolism Is Constrained by the Intracellular Environment

PLoS Pathogens

Volumn 11, Issue 2, 2015, Pages

  VanderVen, Brian C ^a   Fahey, Ruth J ^a   Lee, Wonsik ^a   Liu, Yancheng ^a   Abramovitch, Robert B ^a   Memmott, Christine ^b   Crowe, Adam M ^c   Eltis, Lindsay D ^c   Perola, Emanuele ^b   Deininger, David D ^b   Wang, Tiansheng ^b   Locher, Christopher P ^b   Russell, David G ^a  

^a Department of Obstetrics Gynecology   (United States)

^b VERTEX PHARMACEUTICALS   (United States)

^c UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

2 METHYLCITRATE SYNTHASE; 3 HYDROXY 9,10 SECOANDROSTA 1,3,5(10) TRIENE 9,17 DIONE; CHOLESTEROL; CITRATE SYNTHASE; CYCLIC AMP; DIMETHYLANILINE MONOOXYGENASE; GLUCOSE; ISOCITRATE LYASE; PRION PROTEIN; PROPIONYL COENZYME A; RIFAMPICIN; UNCLASSIFIED DRUG; 2-METHYLCITRATE SYNTHASE; ADENYLATE CYCLASE; BACTERIAL PROTEIN; HYDROXYSTEROID DEHYDROGENASE; LYASE; MIXED FUNCTION OXIDASE; MOLECULAR LIBRARY; TUBERCULOSTATIC AGENT;

ARTICLE; BACTERIAL METABOLISM; CATABOLISM; CELL PROLIFERATION; CHEMICAL ANALYSIS; CHOLESTEROL METABOLISM; CONTROLLED STUDY; DOSE RESPONSE; ENZYME INHIBITION; ENZYME INHIBITOR COMPLEX; ESCHERICHIA COLI; GROWTH INHIBITION; HIGH THROUGHPUT SCREENING; HUMAN; IC50; IMMUNOASSAY; MACROPHAGE; MASS FRAGMENTOGRAPHY; MICROARRAY ANALYSIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PHENOTYPE; POLYMERASE CHAIN REACTION; RADIOASSAY; RESPIROMETRY; SIGNAL TRANSDUCTION; TRANSPOSON; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL LINE; DRUG EFFECTS; GENETICS; GROWTH, DEVELOPMENT AND AGING; IMMUNOLOGY; INTRACELLULAR SPACE; LIPID METABOLISM; METABOLISM; MICROBIAL SENSITIVITY TEST; MICROBIOLOGY; MOLECULAR LIBRARY; MOUSE; PHARMACOLOGY; TUBERCULOSIS, PULMONARY;

BACTERIA (MICROORGANISMS); MYCOBACTERIUM TUBERCULOSIS;

ADENYLYL CYCLASES; ANIMALS; ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; CELL LINE; CHOLESTEROL; CYCLIC AMP; HYDROXYSTEROID DEHYDROGENASES; INTRACELLULAR SPACE; LIPID METABOLISM; MACROPHAGES; MICE; MICROBIAL SENSITIVITY TESTS; MIXED FUNCTION OXYGENASES; MYCOBACTERIUM TUBERCULOSIS; OXO-ACID-LYASES; SMALL MOLECULE LIBRARIES; TUBERCULOSIS, PULMONARY;

EID: 84924351877     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1004679     Document Type: Article

References (56)

1. Russell DG, Barry CE, Flynn JL, (2010) Tuberculosis: What We Don’t Know Can, and Does, Hurt Us. Science 328: 852–856. doi: 10.1126/science.1184784 20466922
2. Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, et al. (2007) Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol 3: 323–324. 17496888
3. Russell DG, (2001) Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol 2: 569–577. 11483990
4. Zhang YJ, Rubin EJ, (2013) Feast or famine: the host-pathogen battle over amino acids. Cell Microbiol 15: 1079–1087. doi: 10.1111/cmi.12140 23521858
5. Gouzy A, Poquet Y, Neyrolles O, (2014) Nitrogen metabolism in Mycobacterium tuberculosis physiology and virulence. Nat Rev Microbiol. doi: 10.1038/nrmicro3423 25564681
6. Homolka S, Niemann S, Russell DG, Rohde KH, (2010) Functional genetic diversity among Mycobacterium tuberculosis complex clinical isolates: delineation of conserved core and lineage-specific transcriptomes during intracellular survival. PLoS Pathog 6: e1000988. doi: 10.1371/journal.ppat.1000988 20628579
7. Rohde KH, Abramovitch RB, Russell DG, (2007) Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. Cell Host Microbe 2: 352–364. 18005756
8. Rohde KH, Veiga DF, Caldwell S, Balazsi G, Russell DG, (2012) Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. PLoS Pathog 8. doi: 10.1371/journal.ppat.1003097 23308068
9. Sassetti CM, Rubin EJ, (2003) Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A 100: 12989–12994. 14569030
10. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, et al. (2003) Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages: Insights into the Phagosomal Environment. The Journal of Experimental Medicine 198: 693–704. 12953091
11. Marrero J, Rhee KY, Schnappinger D, Pethe K, Ehrt S, (2010) Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci U S A 107: 9819–9824. doi: 10.1073/pnas.1000715107 20439709
12. Puckett S, Trujillo C, Eoh H, Marrero J, Spencer J, et al. (2014) Inactivation of fructose-1,6-bisphosphate aldolase prevents optimal co-catabolism of glycolytic and gluconeogenic carbon substrates in Mycobacterium tuberculosis. PLoS Pathog 10: e1004144. doi: 10.1371/journal.ppat.1004144 24851864
13. Trujillo C, Blumenthal A, Marrero J, Rhee KY, Schnappinger D, et al. (2014) Triosephosphate isomerase is dispensable in vitro yet essential for Mycobacterium tuberculosis to establish infection. MBio 5: e00085. doi: 10.1128/mBio.00085-14 24757211
14. Chang JC, Harik NS, Liao RP, Sherman DR, (2007) Identification of Mycobacterial Genes That Alter Growth and Pathology in Macrophages and in Mice. Journal of Infectious Diseases 196: 788–795. 17674323
15. Hu Y, van der Geize R, Besra GS, Gurcha SS, Liu A, et al. (2010) 3-Ketosteroid 9alpha-hydroxylase is an essential factor in the pathogenesis of Mycobacterium tuberculosis. Mol Microbiol 75: 107–121. doi: 10.1111/j.1365-2958.2009.06957.x 19906176
16. Pandey AK, Sassetti CM, (2008) Mycobacterial persistence requires the utilization of host cholesterol. Proceedings of the National Academy of Sciences 105: 4376–4380. doi: 10.1073/pnas.0711159105 18334639
17. Rengarajan J, Bloom BR, Rubin EJ, (2005) Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proceedings of the National Academy of Sciences of the United States of America 102: 8327–8332. 15928073
18. McKinney JD, zu Bentrup KH, Munoz-Elias EJ, Miczak A, Chen B, et al. (2000) Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406: 735–738. 10963599
19. Muñoz-Elías EJ, Upton AM, Cherian J, McKinney JD, (2006) Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Molecular Microbiology 60: 1109–1122. 16689789
20. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL, (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6: 29–40. 17159923
21. Zhang J-H, Chung T, Oldenburg KR, (1999) A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. Journal of Biomolecular Screening 4: 67–73. 10838414
22. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, et al. (1998) Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J Clin Microbiol 36: 362–366. 9466742
23. Bloch H, Segal W, (1956) Biochemical differentiation of Mycobacterium tuberculosis grown in vivo and in vitro. J Bacteriol 72: 132–141. 13366889
24. Munoz-Elias 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. 15895072
25. Cho SH, Warit S, Wan B, Hwang CH, Pauli GF, et al. (2007) Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 51: 1380–1385. 17210775
26. Gould TA, van de Langemheen H, Munoz-Elias EJ, McKinney JD, Sacchettini JC, (2006) Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis. Mol Microbiol 61: 940–947. 16879647
27. Griffin JE, Pandey AK, Gilmore SA, Mizrahi V, McKinney JD, et al. (2012) Cholesterol catabolism by Mycobacterium tuberculosis requires transcriptional and metabolic adaptations. Chem Biol 19: 218–227. doi: 10.1016/j.chembiol.2011.12.016 22365605
28. Savvi S, Warner DF, Kana BD, McKinney JD, Mizrahi V, et al. (2008) Functional Characterization of a Vitamin B12-Dependent Methylmalonyl Pathway in Mycobacterium tuberculosis: Implications for Propionate Metabolism during Growth on Fatty Acids. J Bacteriol 190: 3886–3895. doi: 10.1128/JB.01767-07 18375549
29. Dresen C, Lin LY, D’Angelo I, Tocheva EI, Strynadka N, et al. (2010) A flavin-dependent monooxygenase from Mycobacterium tuberculosis involved in cholesterol catabolism. J Biol Chem 285: 22264–22275. doi: 10.1074/jbc.M109.099028 20448045
30. Capyk JK, Casabon I, Gruninger R, Strynadka NC, Eltis LD, (2011) Activity of 3-ketosteroid 9alpha-hydroxylase (KshAB) indicates cholesterol side chain and ring degradation occur simultaneously in Mycobacterium tuberculosis. J Biol Chem 286: 40717–40724. doi: 10.1074/jbc.M111.289975 21987574
31. Lack NA, Yam KC, Lowe ED, Horsman GP, Owen RL, et al. (2010) Characterization of a carbon-carbon hydrolase from Mycobacterium tuberculosis involved in cholesterol metabolism. J Biol Chem 285: 434–443. doi: 10.1074/jbc.M109.058081 19875455
32. Yam KC, D’Angelo I, Kalscheuer R, Zhu H, Wang JX, et al. (2009) Studies of a ring-cleaving dioxygenase illuminate the role of cholesterol metabolism in the pathogenesis of Mycobacterium tuberculosis. PLoS Pathog 5: e1000344. doi: 10.1371/journal.ppat.1000344 19300498
33. Manjunatha U, Boshoff HI, Barry CE, (2009) The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol 2: 215–218. 19641733
34. Murima P, de Sessions PF, Lim V, Naim AN, Bifani P, et al. (2013) Exploring the mode of action of bioactive compounds by microfluidic transcriptional profiling in mycobacteria. PLoS One 8: e69191. doi: 10.1371/journal.pone.0069191 23935951
35. Balganesh M, Kuruppath S, Marcel N, Sharma S, Nair A, et al. (2010) Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. Antimicrob Agents Chemother. doi: 10.1128/AAC.00942-10 21189351
36. Hartkoorn RC, Uplekar S, Cole ST, (2014) Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58: 2979–2981. doi: 10.1128/AAC.00037-14 24590481
37. Milano A, Pasca MR, Provvedi R, Lucarelli AP, Manina G, et al. (2009) Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb) 89: 84–90. doi: 10.1016/j.tube.2008.08.003 18851927
38. Masiewicz P, Brzostek A, Wolanski M, Dziadek J, Zakrzewska-Czerwinska J, (2012) A novel role of the PrpR as a transcription factor involved in the regulation of methylcitrate pathway in Mycobacterium tuberculosis. PLoS One 7: e43651. doi: 10.1371/journal.pone.0043651 22916289
39. Casabon I, Zhu SH, Otani H, Liu J, Mohn WW, et al. (2013) Regulation of the KstR2 regulon of Mycobacterium tuberculosis by a cholesterol catabolite. Mol Microbiol 89: 1201–1212. doi: 10.1111/mmi.12340 23879670
40. Kendall SL, Withers M, Soffair CN, Moreland NJ, Gurcha S, et al. (2007) A highly conserved transcriptional repressor controls a large regulon involved in lipid degradation in Mycobacterium smegmatis and Mycobacterium tuberculosis. Mol Microbiol 65: 684–699. 17635188
41. de Carvalho LP, Fischer SM, Marrero J, Nathan C, Ehrt S, et al. (2010) Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates. Chem Biol 17: 1122–1131. doi: 10.1016/j.chembiol.2010.08.009 21035735
42. Guo YL, Seebacher T, Kurz U, Linder JU, Schultz JE, (2001) Adenylyl cyclase Rv1625c of Mycobacterium tuberculosis: a progenitor of mammalian adenylyl cyclases. Embo j 20: 3667–3675. 11447108
43. Townsend PD, Holliday PM, Fenyk S, Hess KC, Gray MA, et al. (2009) Stimulation of mammalian G-protein-responsive adenylyl cyclases by carbon dioxide. J Biol Chem 284: 784–791. doi: 10.1074/jbc.M807239200 19008230
44. Pethe K, Sequeira PC, Agarwalla S, Rhee K, Kuhen K, et al. (2010) A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat Commun 1: 57. doi: 10.1038/ncomms1060 20975714
45. Barry CE, Boshoff HI, Dartois V, Dick T, Ehrt S, et al. (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7: 845–855. doi: 10.1038/nrmicro2236 19855401
46. Kim MJ, Wainwright HC, Locketz M, Bekker LG, Walther GB, et al. (2010) Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol Med 2: 258–274. doi: 10.1002/emmm.201000079 20597103
47. Lee HJ, Lang PT, Fortune SM, Sassetti CM, Alber T, (2012) Cyclic AMP regulation of protein lysine acetylation in Mycobacterium tuberculosis. Nat Struct Mol Biol 19: 811–818. doi: 10.1038/nsmb.2318 22773105
48. Nambi S, Badireddy S, Visweswariah SS, Anand GS, (2012) Cyclic AMP-induced conformational changes in mycobacterial protein acetyltransferases. J Biol Chem 287: 18115–18129. doi: 10.1074/jbc.M111.328112 22447926
49. Xu H, Hegde SS, Blanchard JS, (2011) Reversible acetylation and inactivation of Mycobacterium tuberculosis acetyl-CoA synthetase is dependent on cAMP. Biochemistry 50: 5883–5892. doi: 10.1021/bi200156t 21627103
50. Hayden JD, Brown LR, Gunawardena HP, Perkowski EF, Chen X, et al. (2013) Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis. Microbiology 159: 1986–1999. doi: 10.1099/mic.0.068585-0 23813678
51. Nambi S, Gupta K, Bhattacharyya M, Ramakrishnan P, Ravikumar V, et al. (2013) Cyclic AMP-dependent protein lysine acylation in mycobacteria regulates fatty acid and propionate metabolism. J Biol Chem 288: 14114–14124. doi: 10.1074/jbc.M113.463992 23553634
52. Daniel J, Maamar H, Deb C, Sirakova TD, Kolattukudy PE, (2011) Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathog 7: e1002093. doi: 10.1371/journal.ppat.1002093 21731490
53. Lee W, VanderVen BC, Fahey RJ, Russell DG, (2013) Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J Biol Chem 288: 6788–6800. doi: 10.1074/jbc.M112.445056 23306194
54. Singh A, Crossman DK, Mai D, Guidry L, Voskuil MI, et al. (2009) Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response. PLoS Pathog 5: e1000545. doi: 10.1371/journal.ppat.1000545 19680450
55. Owens RM, Hsu FF, VanderVen BC, Purdy GE, Hesteande E, et al. (2006) M. tuberculosis Rv2252 encodes a diacylglycerol kinase involved in the biosynthesis of phosphatidylinositol mannosides (PIMs). Molecular Microbiology 60: 1152–1163. 16689792
56. Prod’hom G, Lagier B, Pelicic V, Hance AJ, Gicquel B, et al. (1998) A reliable amplification technique for the characterization of genomic DNA sequences flanking insertion sequences. FEMS Microbiol Lett 158: 75–81. 9453159