Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in .

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M. tuberculosis (M. tb) survives only if it can acquire iron from its human host, so new therapies for tuberculosis might be discovered if the pathways necessary for iron acquisition are identified. M. tb scavenges iron in two ways: from free iron, or from the blood in the form of heme. To bind free iron, M. tb uses mycobactin, a lipopeptide that tightly binds iron and transports it to the bacterial cytosol. Mycobactin is thought to be required for M. tb virulence, but its biosynthesis is incompletely understood. To investigate mycobactin biosynthesis, we deleted the mbtN and mbtK genes potentially required for generating the mycobactin lipid tail. Then, an organism-wide screen of lipids identified changed molecules that are the direct targets of these genes or have broader downstream functions. MbtK deletion specifically changed the lipid component of mycobactin and created extreme iron-deprivation that prevented growth of M. tb in mice. Unexpectedly, the combination of MbtK loss and iron starvation triggered a global depletion of phospholipids, a key constituent of the bacterial membrane. These studies establish that mycobactins, acting independently of the heme acquisition pathway, impact lipid homeostasis and M. tb survival, supporting efforts to develop host-directed therapies for tuberculosis.

Vyšlo v časopise: Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in .. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004792
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004792

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1. Murray M, Murray A, Murray M, Murray C. The adverse effect of iron repletion on the course of certain infections. British Medical Journal. 1978;2: 1113–1115. 361162

2. Ratledge C. Iron, mycobacteria and tuberculosis. Tuberculosis. 2004;84: 110–130. 14670352

3. Schaible UE, Kaufmann SHE. Iron and microbial infection. Nat Rev Micro. 2004;2: 946–953. 15550940

4. Jones CM, Niederweis M. Mycobacterium tuberculosis Can Utilize Heme as an Iron Source. Journal of Bacteriology. 2011;193: 1767–1770. doi: 10.1128/JB.01312-10 21296960

5. Tullius MV, Harmston CA, Owens CP, Chim N, Morse RP, et al. Discovery and characterization of a unique mycobacterial heme acquisition system. Proceedings of the National Academy of Sciences. 2011;108: 5051–5056. doi: 10.1073/pnas.1009516108 21383189

6. Drakesmith H, Prentice AM. Hepcidin and the Iron-Infection Axis. Science. 2012;338: 768–772. doi: 10.1126/science.1224577 23139325

7. Gobin J, Moore CH, Reeve JR, Wong DK, Gibson BW, et al. Iron acquisition by Mycobacterium tuberculosis: isolation and characterization of a family of iron-binding exochelins. Proceedings of the National Academy of Sciences of the United States of America. 1995;92: 5189–5193. 7761471

8. Snow GA. The Structure of Mycobactin P, a Growth Factor for Mycobacterium johnei, and the Significance of its Iron Complex. Biochemistry Journal. 1965;94: 160–165.

9. De Voss JJ, Rutter K, Schroeder BG, Su H, Zhu Y, et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. PNAS. 2000;97: 1252–1257. 10655517

10. Reddy PV, Puri RV, Chauhan P, Kar R, Rohilla A, et al. Disruption of Mycobactin Biosynthesis Leads to Attenuation of Mycobacterium tuberculosis for Growth and Virulence. Journal of Infectious Diseases. 2013;208: 1255–1265. doi: 10.1093/infdis/jit250 23788726

11. Wells RM, Jones CM, Xi Z, Speer A, Danilchanka O, et al. Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis. PLoS Pathog. 2013;9: e1003120. doi: 10.1371/journal.ppat.1003120 23431276

12. Jones CM, Wells RM, Madduri AVR, Renfrow MB, Ratledge C, et al. Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling. Proceedings of the National Academy of Sciences. 2014;111: 1945–1950. doi: 10.1073/pnas.1311402111 24497493

13. Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Molecular Microbiology. 2003;48: 77–84. 12657046

14. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, et al. Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages. J Exp Med. 2003;198: 693–704. 12953091

15. Madigan C, Cheng T-Y, Layre E, Young D, McConnell M, et al. Lipidomic discovery of deoxysiderophores reveals a revised pathway of mycobactin biosynthesis in M. tuberculosis. Proceedings of the National Academy of Sciences. 2012;109: 1257–1262. doi: 10.1073/pnas.1109958109 22232695

16. Krithika R, Marathe U, Saxena P, Ansari MZ, Mohanty D, et al. A genetic locus required for iron acquisition in Mycobacterium tuberculosis. PNAS. 2006;103: 2069–2074. 16461464

17. Quadri LEN, Sello J, Keating TA, Weinreb PH, Walsh CT. Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chemistry & Biology. 1998;5: 631–645.

18. Rodriguez G, Voskuil M, Gold B, Schoolnik G, Smith I. ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun. 2002;70: 3371–3381. 12065475

19. Card GL, Peterson NA, Smith CA, Rupp B, Schick BM, et al. The Crystal Structure of Rv1347c, a Putative Antibiotic Resistance Protein from Mycobacterium tuberculosis, Reveals a GCN5-related Fold and Suggests an Alternative Function in Siderophore Biosynthesis. J Biol Chem. 2005;280: 13978–13986. 15695811

20. Chavadi SS, Stirrett KL, Edupuganti UR, Vergnolle O, Sadhanandan G, et al. Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster. J Bacteriol. 2011: 05811–05811.

21. McMahon MD, Rush JS, Thomas MG. Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis. Journal of Bacteriology. 2012;194: 2809–2818. doi: 10.1128/JB.00088-12 22447909

22. Frankel BA, Blanchard JS. Mechanistic analysis of Mycobacterium tuberculosis Rv1347c, a lysine N[epsilon]-acyltransferase involved in mycobactin biosynthesis. Archives of Biochemistry and Biophysics. 2008;477: 259–266. doi: 10.1016/j.abb.2008.05.013 18539130

23. De Voss JJ, Rutter K, Schroeder BG, Barry CE III. Iron Acquisition and Metabolism by Mycobacteria. J Bacteriol. 1999;181: 4443–4451. 10419938

24. Snow GA. Mycobactins: iron-chelating growth factors from mycobacteria. Microbiol Mol Biol Rev. 1970;34: 99–125.

25. Moody DB, Young DC, Cheng T-Y, Rosat J-P, Roura-mir C, et al. T Cell Activation by Lipopeptide Antigens. Science. 2004;303: 527–531. 14739458

26. Sartain MJ, Dick DL, Rithner CD, Crick DC, Belisle JT. Lipidomic analyses of Mycobacterium tuberculosis based on accurate mass measurements and the novel Mtb LipidDB. Journal of Lipid Research. 2011;52: 861–872. doi: 10.1194/jlr.M010363 21285232

27. Layre E, Moody DB. Lipidomic profiling of model organisms and the world's major pathogens. Biochimie. 2013;95: 109–115. doi: 10.1016/j.biochi.2012.08.012 22971440

28. Layre E, Hong S, Sweet L, Madigan CA, Desjardins D, et al. A comparative lipidomics platform for Mycobacterium tuberculosis provides chemotaxonomic analysis for biomarker discovery. Chemistry & Biology. 2011;18: 1837–1549.

29. Murry JP, Pandey AK, Sassetti CM, Rubin EJ. Phthiocerol Dimycocerosate Transport Is Required for Resisting Interferon-Gamma Independent Immunity. The Journal of Infectious Diseases. 2009;200: 774–782. doi: 10.1086/605128 19622047

30. Siegrist M, Unnikrishnan M, McConnell M, Borowsky M, TY TC, et al. Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition. PNAS. 2009;106: 18792–18797. doi: 10.1073/pnas.0900589106 19846780

31. Morris P, Marinelli LJ, Jacobs-Sera D, Hendrix RW, Hatfull GF. Genomic Characterization of Mycobacteriophage Giles: Evidence for Phage Acquisition of Host DNA by Illegitimate Recombination. J Bacteriol. 2008;190: 2172–2182. doi: 10.1128/JB.01657-07 18178732

32. Gobin J, Wong DK, Gibson BW, Horwitz MA. Characterization of Exochelins of theMycobacterium bovis Type Strain and BCG Substrains. Infection and Immunity. 1999;67: 2035–2039. 10085056

33. Smith CA, Want EJ, O'Maille G, Abagyan R, Siuzdak G. XCMS: Processing Mass Spectrometry Data for Metabolite Profiling Using Nonlinear Peak Alignment, Matching, and Identification. Analytical Chemistry. 2006;78: 779–787. 16448051

34. Crosa JH, Walsh CT. Genetics and Assembly Line Enzymology of Siderophore Biosynthesis in Bacteria. Microbiol Mol Biol Rev. 2002;66: 223–249. 12040125

35. Quadri LEN, Ratledge C (2005) Iron Metabolism in the Tubercle Bacillus and Other Mycobacteria. In: Cole ST, Eisenach KD, McMurray DN, William R Jacobs J, editors. Tuberculosis and the Tubercle Bacillus. Washington, D.C.: ASM Press. pp. 341–357.

36. Ferreras JA, Ryu J-S, Di Lello F, Tan DS, Quadri LEN. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol. 2005;1: 29–32. 16407990

37. Blumenthal A, Trujillo C, Ehrt S, Schnappinger D. Simultaneous Analysis of Multiple Mycobacterium tuberculosis Knockdown Mutants In Vitro and In Vivo. PLoS ONE. 2010;5: e15667. doi: 10.1371/journal.pone.0015667 21203517

38. Galagan JE, Minch K, Peterson M, Lyubetskaya A, Azizi E, et al. The Mycobacterium tuberculosis regulatory network and hypoxia. Nature. 2013;499: 178–183. doi: 10.1038/nature12337 23823726

39. Farhana A, Guidry L, Srivastava A, Singh A, Hondalus MK, et al. (2010) Reductive Stress in Microbes: Implications for Understanding Mycobacterium tuberculosis Disease and Persistence. In: Robert KP, editor. Advances in Microbial Physiology: Academic Press. pp. 43–117. doi: 10.1016/B978-0-12-381045-8.00002-3 21078441

40. Vilcheze C, Hartman T, Weinrick B, Jacobs WR. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nature Communications. 2013;4: 1881. doi: 10.1038/ncomms2898 23695675

41. Honaker RW, Dhiman RK, Narayanasamy P, Crick DC, Voskuil MI. DosS Responds to a Reduced Electron Transport System To Induce the Mycobacterium tuberculosis DosR Regulon. Journal of Bacteriology. 2010;192: 6447–6455. doi: 10.1128/JB.00978-10 20952575

42. Kumar A, Farhana A, Guidry L, Saini V, Hondalus M, et al. Redox homeostasis in mycobacteria: the key to tuberculosis control? Expert Reviews in Molecular Medicine. 2011;13.

43. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393: 537–544. 9634230

44. Khayatt BI, Overmars L, Siezen RJ, Francke C. Classification of the Adenylation and Acyl-Transferase Activity of NRPS and PKS Systems Using Ensembles of Substrate Specific Hidden Markov Models. PLoS ONE. 2013;8: e62136. doi: 10.1371/journal.pone.0062136 23637983

45. Donadio S, Monciardini P, Sosio M. Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics. Natural Product Reports. 2007;24: 1073–1109. 17898898

46. Jones CM, Wells RM, Madduri AVR, Renfrow MB, Ratledge C, et al. Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling. Proceedings of the National Academy of Sciences. 2014;111: 1945–1950. doi: 10.1073/pnas.1311402111 24497493

47. Coleman MT, Maiello P, Tomko J, Frye LJ, Fillmore D, et al. Early Changes by 18Fluorodeoxyglucose Positron Emission Tomography Coregistered with Computed Tomography Predict Outcome after Mycobacterium tuberculosis Infection in Cynomolgus Macaques. Infection and Immunity. 2014;82: 2400–2404. doi: 10.1128/IAI.01599-13 24664509

48. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2014;20: 75–79. doi: 10.1038/nm.3412 24336248

49. Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, et al. Microenvironments in Tuberculous Granulomas Are Delineated by Distinct Populations of Macrophage Subsets and Expression of Nitric Oxide Synthase and Arginase Isoforms. The Journal of Immunology. 2013;191: 773–784. doi: 10.4049/jimmunol.1300113 23749634

50. Via LE, Schimel D, Weiner DM, Dartois V, Dayao E, et al. Infection Dynamics and Response to Chemotherapy in a Rabbit Model of Tuberculosis using [18F]2-Fluoro-Deoxy-d-Glucose Positron Emission Tomography and Computed Tomography. Antimicrobial Agents and Chemotherapy. 2012;56: 4391–4402. doi: 10.1128/AAC.00531-12 22687508

51. Bacon J, Dover LG, Hatch KA, Zhang Y, Gomes JM, et al. Lipid composition and transcriptional response of Mycobacterium tuberculosis grown under iron-limitation in continuous culture: identification of a novel wax ester. Microbiology. 2007;153: 1435–1444. 17464057

52. Baek S-H, Li AH, Sassetti CM. Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity. PLoS Biol. 2011;9: e1001065. doi: 10.1371/journal.pbio.1001065 21629732

53. Singh A, Crossman DK, Mai D, Guidry L, Voskuil MI, et al. Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response. PLoS Pathog. 2009;5: e1000545. doi: 10.1371/journal.ppat.1000545 19680450

54. Saini V, Farhana A, Glasgow JN, Steyn AJC. Iron sulfur cluster proteins and microbial regulation: implications for understanding tuberculosis. Current Opinion in Chemical Biology. 2012;16: 45–53. doi: 10.1016/j.cbpa.2012.03.004 22483328

55. Lun S, Guo H, Adamson J, Cisar JS, Davis TD, et al. Pharmacokinetic and In Vivo Efficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice. Antimicrobial Agents and Chemotherapy. 2013;57: 5138–5140. doi: 10.1128/AAC.00918-13 23856770

56. Jacobs W, Kalpana G, Cirillo J, Pascopella L, Snapper S, et al. Genetic systems for mycobacteria. Methods in Enzymology. 1991;204: 537–555. 1658570