• No results found

Chapter 7 – General Discussion

7.6 Conclusions

FDORs are extremely diverse in mycobacteria, and include functional roles as quinone reductases, lipid saturases, heme oxygenases and biliverdin reductases that can contribute to mycobacterial persistence and pathogenesis. These functions are determined by their cofactor specificities and structural characterisation shows flexible active sites that allow promiscuous activity with a wide variety of substrates in some FDORs. Detailed analysis of the catalytic mechanism of the F420 dependent biliverdin

reductases suggest that it proceeds similar to the nicotinamide dependent reaction in the equivalent mammalian proteins. Finally, the abundance of F420 producing bacteria

indicates physiological roles of the FDORs in these organisms in addition to their involvement in mycobacterial persistence.

References

173

References

174

Abdalla, M.Y., Ahmad, I.M., Switzer, B. & Britigan, B.E., 2015. Induction of heme oxygenase-1 contributes to survival of Mycobacterium abscessus in human macrophages-like THP-1 cells. Redox Biology, 4(0), pp.328–339.

Accinelli, C., Abbas, H.K., Zablotowicz, R.M. & Wilkinson, J.R., 2008. Aspergillus flavus aflatoxin occurrence and expression of aflatoxin biosynthesis genes in soil. Canadian journal of microbiology, 54(5), pp.371–379.

Ahmed, F.H., Carr, P.D., Lee, B.M., Afriat-Jurnou, L., Mohamed, A.E., Hong, N.-S., Flanagan, J., Taylor, M.C., Greening, C. & Jackson, C.J., 2015. Sequence- Structure-Function Classification of a Catalytically Diverse Oxidoreductase Superfamily in Mycobacteria. Journal of molecular biology, 427(22), pp.3554– 3571.

Ahmed, F.H., Mohamed, A.E., Carr, P.D., Lee, B.M., Condic-Jurkic, K., O’Mara, M.L. & Jackson, C.J., 2016. Rv2074 is a novel F 420 H 2 -dependent biliverdin reductase

in Mycobacterium tuberculosis. Protein Science, 25(9), pp.1692–1709.

Angle, J.S., 1986. Aflatoxin decomposition in various soils. Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes, 21(4), pp.277–288.

Berney, M. & Cook, G.M., 2010. Unique Flexibility in Energy Metabolism Allows Mycobacteria to Combat Starvation and Hypoxia. PloS One, 5(1), p.e8614.

Berney, M., Greening, C., Conrad, R., Jacobs, W.R. & Cook, G.M., 2014. An obligately aerobic soil bacterium activates fermentative hydrogen production to survive reductive stress during hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 111(31), pp.11479–11484.

Blair, H.A. & Scott, L.J., 2015. Delamanid: a review of its use in patients with multidrug-resistant tuberculosis. Drugs, 75(1), pp.91–100.

Bloemberg, G. V, Keller, P.M., Stucki, D., Trauner, A., Borrell, S., Latshang, T., Coscolla, M., Rothe, T., Homke, R., Ritter, C., Fieldmann, J., Schulthess, B., Gagneux, S. & Bottger, E.C., 2015. Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis. The New England Journal of Medicine, 373, pp.1986–1988.

References

175

Boon, C. & Dick, T., 2002. Mycobacterium bovis BCG Response Regulator Essential for Hypoxic Dormancy. Journal of Bacteriology, 184(24), pp.6760–6767.

Ceh, K., Demmer, U., Warkentin, E., Moll, J., Thauer, R.K., Shima, S. & Ermler, U., 2009. Structural Basis of the Hydride Transfer Mechanism in F420-Dependent

Methylenetetrahydromethanopterin Dehydrogenase. Biochemistry, 48(42), pp.10098–10105.

Cellitti, S.E., Shaffer, J., Jones, D.H., Mukherjee, T., Gurumurthy, M., Bursulaya, B., Boshoff, H.I., Choi, I., Nayyar, A., Lee, Y.S., Cherian, J., Niyomrattanakit, P., Dick, T., Manjunatha, U.H., Barry III, C.E., Spraggon, G. & Geierstanger, B.H., 2012. Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824. Structure, 20(1), pp.101–112.

Chan, J., Xing, Y., Magliozzo, R.S. & Bloom, B.R., 1992. Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. The Journal of experimental medicine, 175(4), pp.1111–1122.

Chaves, A.S., Rodrigues, M.F., Mattos, A.M.M. & Teixeira, H.C., 2015. Challenging Mycobacterium tuberculosis dormancy mechanisms and their immunodiagnostic potential. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 19(6), pp.636–642.

Choi, K.-P., Bair, T.B., Bae, Y.-M. & Daniels, L., 2001. Use of Transposon Tn5367 Mutagenesis and a Nitroimidazopyran-Based Selection System To Demonstrate a Requirement for fbiA and fbiB in Coenzyme F420 Biosynthesis by Mycobacterium

bovis BCG. Journal of Bacteriology, 183(24), pp.7058–7066.

Choi, K.-P., Kendrick, N. & Daniels, L., 2002. Demonstration that fbiC Is Required by Mycobacterium bovis BCG for Coenzyme F420 and FO Biosynthesis. Journal of

Bacteriology, 184(9), pp.2420–2428.

Cole, S.T., Eiglmeier, K., Parkhill, J., James, K.D., Thomson, N.R., Wheeler, P.R., Honore, N., Garnier, T., Churcher, C., Harris, D., Mungall, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R.M., Devlin, K., Duthoy, S., Feltwell, T., Fraser, A., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Lacroix,

References

176

C., Maclean, J., Moule, S., Murphy, L., Oliver, K., Quail, M.A., Rajandream, M.A., Rutherford, K.M., Rutter, S., Seeger, K., Simon, S., Simmonds, M., Skelton, J., Squares, R., Squares, S., Stevens, K., Taylor, K., Whitehead, S., Woodward, J.R. & Barrell, B.G., 2001. Massive gene decay in the leprosy bacillus. Nature, 409(6823), pp.1007–1011.

Cook, G.M., Greening, C., Hards, K. & Berney, M., 2014. Chapter One - Energetics of Pathogenic Bacteria and Opportunities for Drug Development. In K. P. Robert, ed. Advances in Microbial Physiology. Academic Press, pp. 1–62.

Cousins, F.B., 1960. The prosthetic group of a chromoprotin from mycobacteria. Biochimica et Biophysica Acta, 40, pp.532–534.

Crain, A. V & Broderick, J.B., 2013. Flavodoxin cofactor binding induces structural changes that are required for protein–protein interactions with NADP+

oxidoreductase and pyruvate formate-lyase activating enzyme. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1834(12), pp.2512–2519. Crellin, P.K., Luo, C.-Y. & Morita, Y.S., 2013. Lipid Metabolism. Edited by Baez,

R.V., InTech.

Daniel, J., Maamar, H., Deb, C., Sirakova, T.D. & Kolattukudy, P.E., 2011. Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathogens, 7(6), p.e1002093.

Dubnau, E., Chan, J., Raynaud, C., Mohan, V.P., Lanéelle, M.A., Yu, K., Quémard, A., Smith, I. & Daffé, M., 2000. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Molecular microbiology, 36(3), pp.630– 637.

Ebert, S., Fischer, P. & Knackmuss, H.-J., 2001. Converging catabolism of 2,4,6- trinitrophenol (picric acid) and 2,4-dinitrophenol by Nocardioides simplex FJ2-1A. Biodegradation, 12(5), pp.367–376.

Forrellad, M.A., Klepp, L.I., Gioffré, A., Sabio y García, J., Morbidoni, H.R., de la Paz Santangelo, M., Cataldi, A.A. & Bigi, F., 2013. Virulence factors of the Mycobacterium tuberculosis complex. Virulence, 4(1), pp.3–66.

References

177

Fu, G., Liu, H. & Doerksen, R.J., 2012. Molecular modeling to provide insight into the substrate binding and catalytic mechanism of human biliverdin-IXα reductase. The journal of physical chemistry. B, 116(32), pp.9580–9594.

Gengenbacher, M. & Kaufmann, S.H.E., 2012. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiology Reviews, 36(3), pp.514–532.

Gillespie, S.H., 2002. Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective. Antimicrobial Agents and Chemotherapy, 46(2), pp.267–274.

Graham, D.E. & Xu, H., 2003. Identification of the 7,8-didemethyl-8-hydroxy-5- deazariboflavin synthase required for coenzyme F420 biosynthesis. Archives of

Microbiology, 180(6), pp.455–464.

Graupner, M. & White, R.H., 2001. Biosynthesis of the Phosphodiester Bond in Coenzyme F420 in the Methanoarchaea. Biochemistry, 40(36), pp.10859–10872.

Graupner, M., Xu, H. & White, R.H., 2002. Characterization of the 2-Phospho-l-lactate Transferase Enzyme Involved in Coenzyme F420 Biosynthesis in Methanococcus

jannaschii. Biochemistry, 41(11), pp.3754–3761.

Greening, C., Ahmed, F.H., Mohamed, A.E., Lee, B.M., Pandey, G., Warden, A.C., Scott, C., Oakeshott, J.G., Taylor, M.C. & Jackson, C.J., 2016. F420- and Fo-

dependent redox reactions: physiology, biochemistry, and applications. Microbiology and Molecular Biology Reviews, 80(2), pp. 451-493.

Griffin, J.E., Gawronski, J.D., Dejesus, M.A., Ioerger, T.R., Akerley, B.J. & Sassetti, C.M., 2011. High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. PLoS pathogens, 7(9), p.e1002251.

Grochowski, L.L., Xu, H. & White, R.H., 2008. Identification and Characterization of the 2-Phospho-l-lactate Guanylyltransferase Involved in Coenzyme F420

Biosynthesis. Biochemistry, 47(9), pp.3033–3037.

Guerra-Lopez, D., Daniels, L. & Rawat, M., 2007. Mycobacterium smegmatis mc2 155 fbiC and MSMEG_2392 are involved in triphenylmethane dye decolorization and coenzyme F420 biosynthesis. Microbiology, 153(8), pp.2724–2732.

References

178

Gurumurthy, M., Rao, M., Mukherjee, T., Rao, S.P.S., Boshoff, H.I., Dick, T., Barry, C.E. & Manjunatha, U.H., 2013. A novel F420-dependent anti-oxidant mechanism

protects Mycobacterium tuberculosis against oxidative stress and bactericidal agents. Molecular Microbiology, 8(4), pp.744–755.

Hartman, T., Weinrick, B., Vilchèze, C., Berney, M., Tufariello, J., Cook, G.M. & Jacobs Jr., W.R., 2014. Succinate Dehydrogenase is the Regulator of Respiration in Mycobacterium tuberculosis. PLoS Pathogens, 10(11), p.e1004510.

Hasan, M.R., Rahman, M., Jaques, S., Purwantini, E. & Daniels, L., 2010. Glucose 6- Phosphate Accumulation in Mycobacteria. Journal of Biological Chemistry, 285(25), pp.19135–19144.

Hilario, E., Li, Y., Niks, D. & Fan, L., 2012. The structure of a Xanthomonas general stress protein involved in citrus canker reveals its flavin-binding property. Acta Crystallographica Section D, 68(7), pp.846–853.

Hsieh, Y.-C., Chia, T., Fun, H.-K. & Chen, C.-J., 2013. Crystal Structure of Dimeric Flavodoxin from Desulfovibrio gigas Suggests a Potential Binding Region for the Electron-Transferring Partner. International Journal of Molecular Sciences, 14(1), p.1667.

Hu, Y., Jiang, F., Guo, Y., Shen, X., Zhang, Y., Zhang, R., Guo, G., Mao, X., Zou, Q. & Wang, D.-C., 2011. Crystal Structure of HugZ, a Novel Heme Oxygenase from Helicobacter pylori. Journal of Biological Chemistry, 286(2), pp.1537–1544. Jain, S., Lamichhane, G., Nimmagadda, S., Pomper, M.G. & Bishai, W.R., 2008.

Antibiotic Treatment of Tuberculosis: Old Problems, New Solutions. Microbe, 3(6), p.285.

Jiang, F., Hu, Y., Guo, Y., Guo, G., Zou, Q.-M. & Wang, D.-C., 2009. Crystallization and preliminary crystallographic studies of Helicobacter pylori HugZ, a novel haem oxygenase. Acta Crystallographica Section F, 65(4), pp.376–378.

Kaur, H., Hughes, M.N., Green, C.J., Naughton, P., Foresti, R. & Motterlini, R., 2003. Interaction of bilirubin and biliverdin with reactive nitrogen species. FEBS letters, 543(1-3), pp.113–119.

References

179

Kitamura, M., Terakawa, K., Inoue, H., Hayashida, T., Suto, K., Morimoto, Y., Yasuoka, N., Shibata, N. & Higuchi, Y., 2007. Determination of the Role of the Carboxyl-terminal Leucine-122 in FMN-binding Protein by Mutational and Structural Analysis. Journal of Biochemistry, 141(4), pp.459–468.

Kumar, A., Deshane, J.S., Crossman, D.K., Bolisetty, S., Yan, B.-S., Kramnik, I., Agarwal, A. & Steyn, A.J.C., 2008. Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon. The Journal of biological chemistry, 283(26), pp.18032–18039.

Lapalikar, G. V, Taylor, M.C., Warden, A.C., Scott, C., Russell, R.J. & Oakeshott, J.G., 2012a. F420-H2-Dependent Degradation of Aflatoxin and other Furanocoumarins Is

Widespread throughout the Actinomycetales. PloS One, 7(2), p.e30114.

Lapalikar, G. V, Taylor, M.C., Warden, A.C., Onagi, H., Hennessy, J.E., Mulder, R.J., Scott, C., Brown, S.E., Russell, R.J., Easton, C.J. & Oakeshott, J.G., 2012b. Cofactor promiscuity among F420-dependent reductases enables them to catalyse

both oxidation and reduction of the same substrate. Catalysis Science & Technology, 2(8), pp.1560–1567.

Leiros, H.-K.S., Kozielski-Stuhrmann, S., Kapp, U., Terradot, L., Leonard, G.A. & McSweeney, S.M., 2004. Structural Basis of 5-Nitroimidazole Antibiotic Resistance: The crystal structure of NimA from Deinococcus radiodurans. Journal of Biological Chemistry, 279(53), pp.55840–55849.

Li, C. & Stocker, R., 2009. Heme oxygenase and iron: from bacteria to humans. Redox

report : communications in free radical research, 14(3), pp.95–101.

Li, H., Graupner, M., Xu, H. & White, R.H., 2003. CofE Catalyzes the Addition of Two Glutamates to F420-0 in F420 Coenzyme Biosynthesis in Methanococcus jannaschii.

Biochemistry, 42(32), pp.9771–9778.

Maines, M.D., 1988. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2(10), pp.2557–2568.

Målen, H., Berven, F.S., Fladmark, K.E. & Wiker, H.G., 2007. Comprehensive analysis of exported proteins from Mycobacterium tuberculosis H37Rv. Proteomics, 7(10), pp.1702–1718.

References

180

Målen, H., Pathak, S., Søfteland, T., de Souza, G.A. & Wiker, H.G., 2010. Definition of novel cell envelope associated proteins in Triton X-114 extracts of Mycobacterium tuberculosis H37Rv. BMC microbiology, 10(1), p.132.

Manjunatha, U., Boshoff, H.I. & Barry, C.E., 2009. The mechanism of action of PA- 824: Novel insights from transcriptional profiling. Communicative & integrative biology, 2(3), pp.215–218.

Mashalidis, E.H., Gittis, A.G., Tomczak, A., Abell, C., Barry, C.E. & Garboczi, D.N., 2015. Molecular insights into the binding of coenzyme F420 to the conserved

protein Rv1155 from Mycobacterium tuberculosis. Protein Science, 24(5), pp.740– 792.

McGarvey, J.A. & Bermudez, L.E., 2001. Phenotypic and Genomic Analyses of the Mycobacterium avium Complex Reveal Differences in Gastrointestinal Invasion and Genomic Composition. Infection and Immunity, 69(12), pp.7242–7249.

Mohamed, A.E., Ahmed, F.H., Arulmozhiraja, S., Lin, C.Y., Taylor, M.C., Krausz, E.R., Jackson, C.J. & Coote, M.L., 2016. Protonation state of F420H2 in the

prodrug-activating deazaflavin dependent nitroreductase (Ddn) from Mycobacterium tuberculosis. Molecular bioSystems, 12(4), pp.1110–1113.

Nambu, S., Matsui, T., Goulding, C.W., Takahashi, S. & Ikeda-Saito, M., 2013. A new way to degrade heme: the Mycobacterium tuberculosis enzyme Mhud catalyzes heme degradation without generating CO. Journal of Biological Chemistry, 288(14), pp.10101–10109.

Nelson-Sathi, S., Sousa, F.L., Roettger, M., Lozada-Chávez, N., Thiergart, T., Janssen, A., Bryant, D., Landan, G., Schönheit, P., Siebers, B., McInerney, J.O. & Martin, W.F., 2015. Origins of major archaeal clades correspond to gene acquisitions from bacteria. Nature, 517(7532), pp.77–80.

Ney, B., Ahmed, F.H., Carere, C.R., Biswas, A., Warden, A.C., Morales, S.E., Pandey, G., Watt, S.J., Oakeshott, J.G., Taylor, M.C., Stott, M.B., Jackson, C.J. & Greening, C., 2016. The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria. The ISME Journal. doi: 10.1038/ismej.2016.100.

References

181

Park, H.-D., Guinn, K.M., Harrell, M.I., Liao, R., Voskuil, M.I., Tompa, M., Schoolnik, G.K. & Sherman, D.R., 2003. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Molecular microbiology, 48(3), pp.833–843.

Purwantini, E. & Daniels, L., 1998. Molecular Analysis of the Gene Encoding F420-

Dependent Glucose-6-Phosphate Dehydrogenase from Mycobacterium smegmatis. Journal of Bacteriology, 180(8), pp.2212–2219.

Purwantini, E. & Daniels, L., 1996. Purification of a novel coenzyme F420-dependent

glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis. Journal of Bacteriology, 178(10), pp.2861–2866.

Purwantini, E. & Mukhopadhyay, B., 2009. Conversion of NO2 to NO by reduced

coenzyme F420 protects mycobacteria from nitrosative damage. Proceedings of the

National Academy of Sciences of the United States of America, 106(15), pp.6333– 6338.

Purwantini, E. & Mukhopadhyay, B., 2013. Rv0132c of Mycobacterium tuberculosis encodes a coenzyme F420-dependent hydroxymycolic acid dehydrogenase. PloS

one, 8(12), p.e81985.

Raux, E., Schubert, H.L. & Warren, M.J., 2000. Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum. Cellular and molecular life sciences : CMLS, 57(13- 14), pp.1880–1893.

Rengarajan, J., Bloom, B.R. & Rubin, E.J., 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(23), pp.8327–8332.

Safo, M.K., Mathews, I., Musayev, F.N., di Salvo, M.L., Thiel, D.J., Abraham, D.J. & Schirch, V., 2000. X-ray structure of Escherichia coli pyridoxine 5′-phosphate oxidase complexed with FMN at 1.8 Å resolution. Structure, 8(7), pp.751–762. Sassetti, C.M., Boyd, D.H. & Rubin, E.J., 2003. Genes required for mycobacterial

growth defined by high density mutagenesis. Molecular Microbiology, 48(1), pp.77–84.

References

182

Schué, M., Maurin, D., Dhouib, R., N′Goma, J.-C.B., Delorme, V., Lambeau, G., Carrière, F. & Canaan, S., 2010. Two cutinase-like proteins secreted by Mycobacterium tuberculosis show very different lipolytic activities reflecting their physiological function. The FASEB Journal, 24(6), pp.1893–1903.

Selengut, J.D. & Haft, D.H., 2010. Unexpected Abundance of Coenzyme F420-

Dependent Enzymes in Mycobacterium tuberculosis and Other Actinobacteria. Journal of Bacteriology, 192(21), pp.5788–5798.

Shiloh, M.U., Manzanillo, P. & Cox, J.S., 2008. Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection. Cell host & microbe, 3(5), pp.323–330.

Silva-Gomes, S., Appelberg, R., Larsen, R., Soares, M.P. & Gomes, M.S., 2013. Heme catabolism by heme oxygenase-1 confers host resistance to Mycobacterium infection. Infection and immunity, 81(7), pp.2536–2545.

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., 2008. PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release. Science, 322(5906), pp.1392–1395.

Smith, L.J., Browne, S., Mulholland, A.J. & Mantle, T.J., 2008. Computational and experimental studies on the catalytic mechanism of biliverdin-IXβ reductase. Biochemical journal, 411(3), pp.475–484.

De Souza, G.A., Leversen, N.A., Målen, H. & Wiker, H.G., 2011. Bacterial proteins with cleaved or uncleaved signal peptides of the general secretory pathway. Journal of Proteomics, 75(2), pp.502–510.

Stocker, R., Yamamoto, Y., McDonagh, A.F., Glazer, A.N. & Ames, B.N., 1987. Bilirubin is an antioxidant of possible physiological importance. Science, 235(4792), pp.1043–1046.

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., Kreiswirth, B.N., Barry, C.E. & Baker, W.R., 2000. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature, 405(6789), pp.962–966.

References

183

Tasneen, R., Williams, K., Amoabeng, O., Minkowski, A., Mdluli, K.E., Upton, A.M. & Nuermberger, E.L., 2015. Contribution of the nitroimidazoles PA-824 and TBA- 354 to the activity of novel regimens in murine models of tuberculosis. Antimicrobial agents and chemotherapy, 59(1), pp.129–135.

Taylor, M.C., Jackson, C.J., Tattersall, D.B., French, N., Peat, T.S., Newman, J., Briggs, L.J., Lapalikar, G. V, Campbell, P.M., Scott, C., Russell, R.J. & Oakeshott, J.G., 2010. Identification and characterization of two families of F420H2-dependent

reductases from Mycobacteria that catalyse aflatoxin degradation. Molecular Microbiology, 78(3), pp.561–575.

Udwadia, Z.F., Amale, R.A., Ajbani, K.K. & Rodrigues, C., 2012. Totally Drug- Resistant Tuberculosis in India. Clinical Infectious Diseases, 54(4), pp.579–581. Velayati, A.A., Masjedi, M.R., Farnia, P., Tabarsi, P., Ghanavi, J., ZiaZarifi, A.H. &

Hoffner, S.E., 2009. Emergence of New Forms of Totally Drug-Resistant Tuberculosis Bacilli. Chest, 136(2), pp.420–425.

Wang, P., Kim, W., Pickens, L.B., Gao, X. & Tang, Y., 2012. Heterologous expression and manipulation of three tetracycline biosynthetic pathways. Angewandte Chemie (International ed. in English), 51(44), pp.11136–1140.

Warkentin, E., Mamat, B., Sordel-Klippert, M., Wicke, M., Thauer, R.K., Iwata, M., Iwata, S., Ermler, U. & Shima, S., 2001. Structures of F420H2:NADP+

oxidoreductase with and without its substrates bound. The EMBO journal, 20(23), pp.6561–6569.

WHO, 2015. Global Tuberculosis Report, Geneva.

Xu, N., Ahuja, E.G., Janning, P., Mavrodi, D.V., Thomashow, L.S. & Blankenfeldt, W., 2013. Trapped intermediates in crystals of the FMN-dependent oxidase PhzG provide insight into the final steps of phenazine biosynthesis. Acta Crystallographica Section D, 69(8), pp.1403–1413.

Yuan, Y., Zhu, Y., Crane, D.D. & Barry, C.E., 1998. The effect of oxygenated mycolic

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